N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors

ABSTRACT

The present invention provides N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines derivatives that modulate the activity of phosphoinositide 3-kinases (PI3Ks) and are useful in the treatment of diseases related to the activity of PI3Ks including, for example, inflammatory disorders, immune-based disorders, cancer, and other diseases.

This application claims the benefit of priority of U.S. ProvisionalAppl. No. 61/425,107, filed Dec. 20, 2010, which is incorporated hereinby reference in its entirety.

FIELD OF THE INVENTION

The present invention providesN-(1-(substituted-phenyl)ethyl)-9H-purin-6-amine derivatives thatmodulate the activity of phosphoinositide 3-kinases (PI3Ks) and areuseful in the treatment of diseases related to the activity of PI3Ksincluding, for example, inflammatory disorders, immune-based disorders,cancer, and other diseases.

BACKGROUND OF THE INVENTION

The phosphoinositide 3-kinases (PI3Ks) belong to a large family of lipidsignaling kinases that phosphorylate phosphoinositides at the D3position of the inositol ring (Cantley, Science, 2002,296(5573):1655-7). PI3Ks are divided into three classes (class I, II,and III) according to their structure, regulation and substratespecificity. Class I PI3Ks, which include PI3Kα, PI3Kβ, PI3Kγ, andPI3Kδ, are a family of dual specificity lipid and protein kinases thatcatalyze the phosphorylation of phosphatidylinosito-4,5-bisphosphate(PIP₂) giving rise to phosphatidylinosito-3,4,5-trisphosphate (PIP₃).PIP₃ functions as a second messenger that controls a number of cellularprocesses, including growth, survival, adhesion and migration. All fourclass I PI3K isoforms exist as heterodimers composed of a catalyticsubunit (p110) and a tightly associated regulatory subunit that controlstheir expression, activation, and subcellular localization. PI3Kα,PI3Kβ, and PI3Kδ associate with a regulatory subunit known as p85 andare activated by growth factors and cytokines through a tyrosinekinase-dependent mechanism (Jimenez, et al., J Biol. Chem., 2002,277(44):41556-62) whereas PI3Kγ associates with two regulatory subunits(p101 and p84) and its activation is driven by the activation ofG-protein-coupled receptors (Brock, et al., J. Cell Biol., 2003,160(1):89-99). PI3Kα and PI3Kβ are ubiquitously expressed. In contrast,PI3Kγ and PI3Kδ are predominantly expressed in leukocytes(Vanhaesebroeck, et al., Trends Biochem Sci., 2005, 30(4):194-204).

The differential tissue distribution of the PI3K isoforms factors intheir distinct biological functions. Genetic ablation of either PI3Kα orPI3β results in embryonic lethality, indicating that PI3Kα and PI3Kβhave essential and non-redundant functions, at least during development(Vanhaesebroeck, et al., 2005). In contrast, mice which lack PI3Kγ andPI3Kδ are viable, fertile and have a normal life span although they showan altered immune system. PI3Kγ deficiency leads to impaired recruitmentof macrophages and neutrophils to sites of inflammation as well asimpaired T cell activation (Sasaki, et al., Science, 2000,287(5455):1040-6). PI3Kδ-mutant mice have specific defects in B cellsignaling that lead to impaired B cell development and reduced antibodyresponses after antigen stimulation (Clayton, et al., J Exp Med. 2002,196(6):753-63; Jou, et al., Mol Cell Biol. 2002, 22(24):8580-91;Okkenhaug, et al., Science, 2002, 297(5583):1031-4).

The phenotypes of the PI3Kγ and PI3Kδ-mutant mice suggest that theseenzymes may play a role in inflammation and other immune-based diseasesand this is borne out in preclinical models. PI3Kγ-mutant mice arelargely protected from disease in mouse models of rheumatoid arthritis(RA) and asthma (Camps, et al., Nat. Med. 2005, 11(9):936-43; Thomas, etal., Eur J. Immunol. 2005, 35(4):1283-91). In addition, treatment ofwild-type mice with a selective inhibitor of PI3Kγ was shown to reduceglomerulonephritis and prolong survival in the MRL-lpr model of systemiclupus nephritis (SLE) and to suppress joint inflammation and damage inmodels of RA (Barber, et al., Nat. Med. 2005, 11(9):933-5; Camps, etal., 2005). Similarly, both PI3KS-mutant mice and wild-type mice treatedwith a selective inhibitor of PI3Kδ have been shown to have attenuatedallergic airway inflammation and hyper-responsiveness in a mouse modelof asthma (Ali, et al., Nature. 2004, 431(7011):1007-11; Lee, et al.,FASEB J. 2006, 20(3):455-65) and to have attenuated disease in a modelof RA (Randis, et al., Eur. J. Immunol., 2008, 38(5):1215-24).

In addition to their potential role in inflammatory diseases, all fourclass I PI3K isoforms may play a role in cancer. The gene encoding p110cc is mutated frequently in common cancers, including breast, prostate,colon and endometrial (Samuels, et al., Science, 2004, 304(5670):554;Samuels, et al., Curr Opin Oncol. 2006, 18(1):77-82). Eighty percent ofthese mutations are represented by one of three amino acid substitutionsin the helical or kinase domains of the enzyme and lead to a significantupregulation of kinase activity resulting in oncogenic transformation incell culture and in animal models (Kang, et al., Proc Natl Acad Sci USA.2005, 102(3):802-7; Bader, et al., Proc Natl Acad Sci USA. 2006,103(5):1475-9). No such mutations have been identified in the other PI3Kisoforms although there is evidence that they can contribute to thedevelopment and progression of malignancies. Consistent overexpressionof PI3Kδ is observed in acute myeloblastic leukemia (Sujobert, et al.,Blood, 2005, 106(3):1063-6) and inhibitors of PI3Kδ can prevent thegrowth of leukemic cells (Billottet, et al., Oncogene. 2006,25(50):6648-59). Elevated expression of PI3Kγ is seen in chronic myeloidleukemia (Hickey, et al., J Biol. Chem. 2006, 281(5):2441-50).Alterations in expression of PI3Kβ, PI3Kγ and PI3Kδ have also beenobserved in cancers of the brain, colon and bladder (Benistant, et al.,Oncogene, 2000, 19(44):5083-90; Mizoguchi, et al., Brain Pathol. 2004,14(4):372-7; Knobbe, et al., Neuropathol Appl Neurobiol. 2005,31(5):486-90). Further, these isoforms have all been shown to beoncogenic in cell culture (Kang, et al., 2006).

Thus, new or improved agents which inhibit kinases such as PI3K arecontinually needed for developing new and more effective pharmaceuticalsthat are aimed at augmentation or suppression of the immune andinflammatory pathways (such as immunosuppressive agents for organtransplants), as well as agents for the prevention and treatment ofautoimmune diseases (e.g., multiple sclerosis, rheumatoid arthritis,asthma, type I diabetes, inflammatory bowel disease, Crohn's disease,autoimmune thyroid disorders, Alzheimer's disease, nephritis), diseasesinvolving a hyperactive inflammatory response (e.g., eczema), allergies,lung diseases, cancer (e.g., prostate, breast, leukemia, multiplemyeloma), and some immune reactions (e.g., skin rash or contactdermatitis or diarrhea) caused by other therapeutics. The compounds,compositions, and methods described herein are directed toward theseneeds and others.

SUMMARY

The present invention provides, inter alia, compounds of Formula I:

and pharmaceutically acceptable salts thereof; wherein the variables aredefined infra.

The present invention further provides compositions comprising acompound of the invention, or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.

The present invention also provides methods of modulating an activity ofa PI3K kinase, comprising contacting the kinase with a compound of theinvention, or a pharmaceutically acceptable salt thereof.

The present invention further provides methods of treating a disease ina patient, wherein said disease is associated with abnormal expressionor activity of a PI3K kinase, comprising administering to said patient atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

The present invention further provides methods of treating animmune-based disease in a patient, comprising administering to saidpatient a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof.

The present invention also provides methods of treating a cancer in apatient, comprising administering to said patient a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt thereof.

The present invention further provides methods of treating a lungdisease in a patient, comprising administering to said patient atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof.

The present invention also provides a compound of invention, or apharmaceutically acceptable salt thereof, for use in any of the methodsdescribed herein.

The present invention further provides use of a compound, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for use in any of the methods described herein.

DETAILED DESCRIPTION

The present invention provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein:

Ar is

X is CH or N;

Y is CH or N;

R¹ is selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl areeach optionally substituted by 1, 2, 3, or 4 groups independentlyselected from halo, OH, CN, NR^(1a)R^(2b), C₁₋₆ alkoxy, and C₁₋₆haloalkoxy;

each R^(1a) and R^(2b) is independently selected from H and C₁₋₆ alkyl;

or any R^(1a) and R^(2b) together with the N atom to which they areattached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group, whichis optionally substituted with 1, 2, 3, or 4 substituents independentlyselected from C₁₋₆ alkyl;

R² is selected from halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, -L-(C₁₋₆alkyl), -L-(C₁₋₆ haloalkyl), and -L-(C₁₋₄ alkylene)_(n)-Cy² and —(C₁₋₄alkylene)_(n)-Cy²; wherein said C₁₋₆ alkyl in said C₁₋₆ alkyl and-L-(C₁₋₆ alkyl) is optionally substituted by 1, 2, 3, or 4 independentlyselected R^(2a) groups;

L is O, NR^(B), S, S(O), S(O)₂, C(O), C(O)NR^(B), S(O)NR^(B),S(O)₂NR^(B), NR^(B)C(O), NR^(B)S(O), and NR^(B)S(O)₂;

R^(A) and R^(B) are each independently selected from H and C₁₋₆ alkyl;

Cy² is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is substituted with pindependently selected R^(2a) groups; wherein p is 0, 1, 2, 3, or 4;

each R^(2a) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino,thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino;

R³ is halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, —(C₁₋₄ alkylene)_(n)-Cy³, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(b), NR^(f)C(O)R^(b), NR^(f)C(O)OR^(b),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(f)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), or S(O)₂NR^(C)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(3a) groups;

Cy³ is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3a) groups;

provided that one of the following is true:

(1) R³ is —(C₁₋₄ alkylene)_(n)-Cy³; or

(2) R² is selected from -L-(C₁₋₄ alkylene)_(n)-Cy² and —(C₁₋₄alkylene)_(n)-Cy²; or

(3) R³ is —(C₁₋₄ alkylene)_(n)-Cy³; and R² is selected from -L-(C₁₋₄alkylene)_(n)-Cy² and —(C₁₋₄ alkylene)_(n)-Cy²;

each R^(3a) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, (5-6 memberedheteroaryl)-C₁₋₄ alkyl, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(b), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl,5-6 membered heteroaryl, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, and (5-6 membered heteroaryl)-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom OH, NO₂, CN, halo, C₁₋₆ alkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl,C₁₋₄ alkoxy-C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

R⁴ is selected from H, OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

R⁵ is selected from halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy;

each R^(a), and R^(d) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, and (5-6 memberedheteroaryl)-C₁₋₄ alkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6membered heteroaryl, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, and (5-6 membered heteroaryl)-C₁₋₄ alkyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl,C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino,C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, and (5-6 memberedheteroaryl)-C₁₋₄ alkyl; each optionally substituted with 1, 2, 3, 4, or5 substituents independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)amino sulfonyl, amino sulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino;

each R^(e) is independently selected from H, C₁₋₄ alkyl, CN, OH, C₁₋₄alkoxy, C₁₋₄ alkylsulfonyl, carbamyl, C₁₋₄ alkylcarbamyl, di(C₁₋₄alkyl)carbamyl, and C₁₋₄ alkylcarbonyl;

each R^(f) is independently selected from C₁₋₄ alkylsulfonyl, C₁₋₄alkylcarbonyl and C₁₋₄ alkoxycarbonyl;

n is 0 or 1; and

r is 0 or 1.

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, Ar is

In some embodiments, X is N and Y is CH; or X is CH and Y is N.

In some embodiments, R⁴ is selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino

In some embodiments, R⁴ is selected from H, halo, CN, C₁₋₆ alkyl,cyano-C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In some embodiments, R⁴ is selected from C₁₋₆ alkyl, cyano-C₁₋₆ alkyl,and C₁₋₆ haloalkyl.

In some embodiments, R⁴ is C₁₋₆ alkyl.

In some embodiments, R⁴ is H.

In some embodiments, R⁴ is methyl.

In some embodiments, R⁴ is F.

In some embodiments, R⁴ is Cl.

In some embodiments, R⁴ is CN.

In some embodiments, R¹ is C₁₋₃ alkyl.

In some embodiments, R¹ is methyl.

In some embodiments, R¹ is ethyl.

In some embodiments, R¹ is methyl or ethyl

In some embodiments, R² is —(C₁₋₆ alkyl), —O—(C₁₋₆ alkyl), —O—(C₁₋₄alkylene)_(n)-Cy², or -Cy²; wherein C₁₋₆ alkyl is optionally substitutedby 1, 2, 3, or 4 independently selected R^(2a) groups.

In some embodiments, R² is C₁₋₆ alkyl, —O—(C₁₋₆ alkyl), —O—(C₁₋₄alkylene)_(n)-(4-7 membered heterocycloalkyl), or phenyl; wherein saidphenyl is optionally substituted by 1, 2, 3, or 4 independently selectedR^(2a) groups.

In some embodiments, R² is methyl.

In some embodiments, R² is methoxy.

In some embodiments, R² is ethoxy.

In some embodiments, R² is methoxy or ethoxy.

In some embodiments, R² is Cy².

In some embodiments, R² is phenyl; wherein phenyl is optionallysubstituted by 1, 2, 3, or 4 groups independently selected from halo.

In some embodiments, each R^(2a) is independently selected from OH, NO₂,CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy,amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, each R^(2a) is independently halo.

In some embodiments, R^(A) is H.

In some embodiments, R⁵ is halo.

In some embodiments, R⁵ is Cl.

In some embodiments, R⁵ is Cl, F, methyl or CN.

In some embodiments, R³ is CN, NO₂, Cy³, C(O)NR^(c)R^(d),NR^(f)C(O)OR^(b), NR^(f)S(O)₂R^(b), and NR^(c)C(O)R^(b).

In some embodiments, R³ is Cy³.

In some embodiments, Cy³ is selected from 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3a) groups.

In some embodiments, Cy³ is selected from phenyl, a piperidine ring, a1,3-oxazolidin-2-one ring, an isoxazole ring, a pyrazole ring, atetrazole ring, a triazole ring, a pyridine ring, and a pyrimidine ring;each of which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(1a) groups.

In some embodiments, Cy³ is selected from phenyl, a piperidine ring, apyrrolidon-2-one ring, a 1,3-oxazolidin-2-one ring, an isoxazole ring, apyrazole ring, a tetrazole ring, a triazole ring, a pyridine ring, apyrimidine ring, an azetidine ring, a pyrrole ring, a tetrahydrofuranring, and a morpholin-2-one ring; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3a) groups;

In some embodiments, each R^(3a) is independently selected from halo,CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, (5-6 memberedheteroaryl)-C₁₋₄ alkyl, OR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),NR^(c)R^(d), NR^(c)C(O)R^(b), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); whereinsaid C₁₋₆ alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl,5-6 membered heteroaryl, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, and (5-6 membered heteroaryl)-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, and di(C₁₋₆ alkyl)amino.

In some embodiments, each R^(3a) is independently selected from halo,CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, OR^(a), C(O)R^(b), C(O)NR^(b)R^(d), NR^(b)R^(d),NR^(c)C(O)R^(b), and S(O)₂R^(b); wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl, and 4-7 membered heterocycloalkyl are each optionallysubstituted by 1, 2, 3, or 4 groups independently selected from OH, CN,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,and di(C₁₋₆ alkyl)amino.

In some embodiments:

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl; wherein said C₁₋₆alkyl, C₃₋₇ cycloalkyl, and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy; and

each R^(b) is independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl,and 4-7 membered heterocycloalkyl; each of which is optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆haloalkoxy.

In some embodiments:

each R^(3a) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, (4-7membered heterocycloalkyl)-C₁₋₃ alkyl, (5-6 membered heteroaryl)-C₁₋₃alkyl, OR^(a), C(O)R^(b), C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), and S(O)₂R^(b); wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl, and 4-7 membered heterocycloalkyl are each optionallysubstituted by 1, 2, 3, or 4 groups independently selected from OH, CN,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, and C₃₋₇ cycloalkyl;

each R^(a), and R^(d) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl; wherein saidC₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₂₋₇ heterocycloalkyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, and amino; and

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, and amino.

In some embodiments:

Cy³ is selected from phenyl, a piperidine ring, a pyrrolidon-2-one ring,a 1,3-oxazolidin-2-one ring, an isoxazole ring, a pyrazole ring, atetrazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, anazetidine ring, a pyrrole ring, a tetrahydrofuran ring, and amorpholin-2-one ring; each of which is optionally substituted with 1, 2,3, or 4 independently selected R^(1a) groups;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₂₋₇ heterocycloalkyl areeach optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and amino; and

each R^(1a) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, and amino.

In some embodiments:

Ar is

R¹ is C₁₋₆ alkyl;

R^(A) is H;

R² is —(C₁₋₆ alkyl), —O—(C₁₋₆ alkyl), —O—(C₁₋₄ alkylene)_(n)-Cy², or-Cy²; wherein C₁₋₆ alkyl is optionally substituted by 1, 2, 3, or 4independently selected R^(2a) groups;

Cy² is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2a) groups;

R³ is CN, NO₂, Cy³, C(O)NR^(c)R^(d), NR^(f)C(O)OR^(b), NR^(f)S(O)₂R^(b),and NR^(c)C(O)R^(b);

Cy³ is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3a) groups;

R⁴ is selected from H, halo, C₁₋₆ alkyl, cyano-C₁₋₆ alkyl, and C₁₋₆haloalkyl; and

R⁵ is halo.

In some embodiments:

Ar is

R¹ is C₁₋₆ alkyl;

R^(A) is H;

R² is —(C₁₋₆ alkyl), —O—(C₁₋₆ alkyl), —O—(C₁₋₄ alkylene)_(n)-Cy², or-Cy²; wherein C₁₋₆ alkyl is optionally substituted by 1, 2, 3, or 4independently selected R^(2a) groups;

Cy² is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(2a) groups;

R³ is CN, NO₂, Cy³, C(O)NR^(c)R^(d), NR^(f)C(O)OR^(b), NR^(f)S(O)₂R^(b),and NR^(c)C(O)R^(b);

Cy³ is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(1a) groups;

R⁴ is selected from H, C₁₋₆ alkyl, cyano-C₁₋₆ alkyl, and C₁₋₆ haloalkyl;and

R⁵ is halo;

each R^(2a) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, and di(C₁₋₆ alkyl)amino;

each R^(3a) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, OR^(a),C(O)R^(b), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), andS(O)₂R^(b); wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 4-7 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groupsindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,cyano-C₁₋₆ alkyl, 110-C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₂₋₇ heterocycloalkyl areeach optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; and

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy.

In some embodiments:

Ar is

R¹ is C₁₋₆ alkyl;

R^(A) is H;

R² is C₁₋₆ alkyl, —O—(C₁₋₆ alkyl), —O—(C₁₋₄ alkylene)_(n)-(4-7 memberedheterocycloalkyl), or phenyl; wherein said phenyl is optionallysubstituted by 1, 2, 3, or 4 independently selected R^(2a) groups;

Cy² is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(ea) groups;

R³ is CN, NO₂, Cy³, C(O)NR^(c)R^(d), NR^(f)C(O)OR^(b), NR^(f)S(O)₂R^(b),and NR^(c)C(O)R^(b);

Cy³ is selected from C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3a) groups;

R⁴ is selected from C₁₋₆ alkyl, cyano-C₁₋₆ alkyl, and C₁₋₆ haloalkyl;and

R⁵ is halo;

each R^(2a) is independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, and di(C₁₋₆ alkyl)amino;

each R^(3a) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, OR^(a),C(O)R^(b), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), andS(O)₂R^(b); wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 4-7 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groupsindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₂₋₇ heterocycloalkyl areeach optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; and

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, andC₁₋₆ haloalkoxy.

In some embodiments:

Ar is

R¹ is methyl or ethyl;

R^(A) is H;

R² is selected from C₁₋₆ alkyl, —O—(C₁₋₆ alkyl), —O—(C₁₋₄alkylene)_(n)-(4-7 membered heterocycloalkyl), and phenyl; wherein saidphenyl is optionally substituted by 1, 2, 3, or 4 independently selectedhalo groups;

R³ is selected from CN, NO₂, Cy³, C(O)NR^(c)R^(d), NR^(f)C(O)OR^(b),NR^(f)S(O)₂R^(b), and NR^(c)C(O)R^(b);

Cy³ is selected from phenyl, a piperidine ring, a pyrrolidon-2-one ring,a 1,3-oxazolidin-2-one ring, an isoxazole ring, a pyrazole ring, atetrazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, anazetidine ring, a pyrrole ring, a tetrahydrofuran ring, and amorpholin-2-one ring; each of which is optionally substituted with 1, 2,3, or 4 independently selected R^(3a) groups;

R⁴ is selected from H, halo, C₁₋₃ alkyl, CN, cyano-C₁₋₆ alkyl, and C₁₋₆haloalkyl;

R⁵ is selected from C₁₋₃ alkyl, halo, and CN;

each R^(3a) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, (4-7membered heterocycloalkyl)-C₁₋₃ alkyl, (5-6 membered heteroaryl)-C₁₋₃alkyl, OR^(a), C(O)R^(b), C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), and S(O)₂R^(b); wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl, and 4-7 membered heterocycloalkyl are each optionallysubstituted by 1, 2, 3, or 4 groups independently selected from OH, CN,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, and C₃₋₇ cycloalkyl;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₂₋₇ heterocycloalkyl areeach optionally substituted with 1, 2, 3, 4, or 5 substituentsindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and amino;

each R^(b) is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl; each of which isoptionally substituted with 1, 2, 3, 4, or 5 substituents independentlyselected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, and amino; and

each R^(f) is independently selected from C₁₋₄ alkylcarbonyl and C₁₋₄alkoxycarbonyl.

In some embodiments, the compound is a compound of Formula II:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IIa:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula III or IV:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula V or VI:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula VII or VIII:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula III or IV:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a compound of Formula IXa, FormulaIXb, Formula IXc, Formula IXd, Formula IXe, or Formula IXf:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is selected from:

-   4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile;-   4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide;-   N-[1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethyl]-9H-purin-6-amine;-   4-Chloro-3-(cyanomethyl)-3′-fluoro-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile;-   1-{4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-one;-   1-{4-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-one;-   3-{4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-1,3-oxazolidin-2-one;-   N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}acetamide;-   Dimethyl    {4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}imidodicarbonate;-   N-{1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-N-(methylsulfonyl)methane    sulfonamide;-   N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   1-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one;-   4-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide;-   N-(1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethyl)-9H-purin-6-amine;-   1-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}piperidin-4-ol;-   3′-Chloro-4-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;-   3′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   1-({3′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}carbonyl)azetidine-3-carbonitrile;-   N-{1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[4-Chloro-3′-fluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-[1-(4-Chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;-   N-{1-[4-Chloro-3′,5′-difluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-Chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-Chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;-   (4-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1H-pyrazol-1-yl)acetonitrile;-   N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3-(3,5-dimethylisoxazol-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-3-(2-methoxypyrimidin-5-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}acetamide;-   N-[1-(5-chloro-3′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-[1-(5-chloro-3′,5′-difluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carbonitrile;-   3′-chloro-N-cyclopropyl-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   N-{1-[5-chloro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-[1-(3′,5-dichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-3-(5-chloropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   3,3′-dichloro-6′-methoxy-N,2′-dimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   N-{1-[5-chloro-2-methoxy-6-methyl-4′-(trifluoromethyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-[1-(5-chloro-4′-ethoxy-3′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carbonitrile;-   {3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}acetonitrile;-   N-{1-[5-chloro-2-methoxy-4′-(methoxymethyl)-6-methylbiphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-6-methyl-4′-(1H-pyrazol-1-yl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-3′-(methoxymethyl)-6-methylbiphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-(1-{5-chloro-2-methoxy-4-methyl-3-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   {3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-yl}acetonitrile;-   N-[1-(3′,5,5′-trichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-4-methyl-3-(6-morpholin-4-ylpyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3-(3-fluoro-2-morpholin-4-ylpyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-[1-(5-chloro-2′,5′-difluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-3-(6-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;-   5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}nicotinonitrile;-   3-(4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutanecarbonitrile;-   N-{1-[5-chloro-2-methoxy-4-methyl-3-(5-methylpyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-{1-[3-(6-aminopyridin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridine-2-carbonitrile;-   N-{1-[5-chloro-3-(6-isopropoxypyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   3′-chloro-N-ethyl-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   3′-chloro-3-fluoro-6′-methoxy-N,N,2′-trimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   N-{1-[5-chloro-3′-fluoro-2-methoxy-6-methyl-4′-(pyrrolidin-1-ylcarbonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3′-fluoro-2-methoxy-6-methyl-4′-(morpholin-4-ylcarbonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   3′-chloro-3-fluoro-6′-methoxy-N,2′-dimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   1-({3′-chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}carbonyl)piperidin-4-ol;-   3′-chloro-N-cyclobutyl-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   N-{1-[5-chloro-3-(2-fluoropyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-[1-(3′,5-dichloro-5′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-2′-fluoro-2-methoxy-6-methyl-5′-(trifluoromethyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3-(6-fluoro-5-methylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-[1-(5-chloro-2-methoxy-6-methyl-4′-morpholin-4-ylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-[1-(3′,5-dichloro-4′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-6-methyl-4′-(trifluoromethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-[1-(5-chloro-3′-ethoxy-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-[1-(4′,5-dichloro-3′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-4′-fluoro-2-methoxy-6-methyl-3′-(trifluoromethyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   3′-chloro-4-fluoro-6′-methoxy-N,N,2′-trimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;-   N-[1-(5-chloro-4′-fluoro-2,3′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-[1-(5-chloro-2,3′,4′-trimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-[1-(3′,5-dichloro-2,4′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-3-(2-chloropyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-[1-(4′,5-dichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-3′-(dimethylamino)-2-methoxy-6-methylbiphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-[1-(5-chloro-2,4′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-[1-(5-chloro-2,4′-dimethoxy-3′,6-dimethylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-[1-(5-chloro-2,3′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-yl}acetamide;-   N-[1-(5-chloro-3′,4′-difluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-3-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   3′-chloro-5-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;-   N-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)acetamide;-   5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}nicotinonitrile;-   N-{1-[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5′-chloro-6′-methyl-4-(methylsulfonyl)-1,1′:2′,1″-terphenyl-3′-yl]ethyl}-9H-purin-6-amine;-   N-(1-{4-chloro-6-[2-(dimethylamino)pyrimidin-5-yl]-5-methylbiphenyl-2-yl}ethyl)-9H-purin-6-amine;-   5′-chloro-N-cyclopropyl-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-carboxamide;-   N-{1-[6-(2-aminopyrimidin-5-yl)-4-chloro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   5′-chloro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-carbonitrile;-   N-{1-[4-chloro-6-(2-methoxypyrimidin-5-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{5′-chloro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-yl}acetamide;-   N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1-methyl-1H-pyrazol-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-[1-(4-chloro-3′,5′-difluoro-5-methyl-6-pyridin-3-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;-   5′-chloro-3″,5″-difluoro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-carbonitrile;-   N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-[1-(4-chloro-3′,5′-difluoro-5-methyl-6-pyrimidin-5-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;-   N-{1-[4-chloro-3,5′-difluoro-6-(2-methoxypyrimidin-5-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{5′-chloro-3″,5″-difluoro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-yl}acetamide;-   N-{1-[4-chloro-6-(3,5-dimethyl-1H-pyrazol-4-yl)-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-fluoro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-[1-(3′-ethoxy-5-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;-   N-cyclopropyl-3′-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   N-{1-[5-fluoro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-fluoro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-5-ylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[3-(2-aminopyrimidin-5-yl)-5-fluoro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[4-Chloro-3′,5′-difluoro-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-Chloro-3-(5-chloropyridin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethyl}-9H-purin-6-amine;-   N-[1-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethyl]-9H-purin-6-amine;-   N-{1-[5-Chloro-6-methyl-4′-(methylsulfonyl)-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[4-chloro-3′,5′-difluoro-6-(2-methoxypyrimidin-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{5′-chloro-3″,5″-difluoro-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-yl}acetamide;-   N-[1-(4-chloro-3′,5′-difluoro-6-pyridin-4-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;-   N-[1-(4-chloro-3′,5′-difluoro-6-pyrimidin-5-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;-   N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-3′,5′-difluorobiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5′-chloro-3″,5″-difluoro-4-(methylsulfonyl)-1,1′:2′,1″-terphenyl-3′-yl]ethyl}-9H-purin-6-amine;-   N-{1-[6-(2-aminopyrimidin-5-yl)-4-chloro-3′,5′-difluorobiphenyl-2-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-3-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-{5′-chloro-2′-methoxy-3′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}acetamide;-   N-{1-[5-chloro-2-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-[1-(5-chloro-2-methoxy-3-pyridin-4-ylphenyl)ethyl]-9H-purin-6-amine;-   N-[1-(5-chloro-2-methoxy-3-pyrimidin-5-ylphenyl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-3-(2,6-difluoropyridin-4-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   3,5′-dichloro-2′-methoxy-N-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   N-{1-[5-chloro-3-(2-fluoropyridin-4-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-3-(5-methoxypyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-3-(6-methoxypyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-[1-{3-(2-aminopyrimidin-5-yl)-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3′-methoxy-6-methyl-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3-(5-chloropyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-4-methyl-3-(1-methyl-1H-pyrazol-5-yl)-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3′,4′-dimethoxy-6-methyl-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;-   3,3′-dichloro-N,2′-dimethyl-6′-(2-morpholin-4-ylethoxy)-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;-   N-{1-[5-chloro-4-methyl-3-[5-(morpholin-4-ylcarbonyl)pyridin-3-yl]-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3-(5-methoxypyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;-   N-(5-{3-chloro-2-methyl-6-(2-morpholin-4-ylethoxy)-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)acetamide;-   3′-chloro-5-fluoro-2′-methyl-6′-(2-morpholin-4-ylethoxy)-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;-   N-{1-[5-chloro-3-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-3-(2-methoxypyrimidin-5-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;    and-   N-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;    1. or a pharmaceutically acceptable salt of any of the    aforementioned.

In some embodiment, the compound is selected from:

-   N-[1-(5-chloro-2-methoxy-4-methyl-3-pyridazin-4-ylphenyl)ethyl]-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine;-   N-{1-[3-(1-acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   methyl    3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate;-   3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N-methylazetidine-1-carboxamide;-   N-(1-{5-chloro-2-methoxy-4-methyl-3-[1-(methylsulfonyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-ethoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-9H-purin-6-amine;-   4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,1-dimethyl-1H-pyrrole-2-carboxamide;-   N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-9H-purin-6-amine;-   6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N    N-dimethylpyridine-2-carboxamide;-   6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridazine-4-carboxamide;-   5-{3-chloro-2-cyano-6-ethoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;-   6-chloro-3-ethoxy-2-[6-(1-hydroxyethyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;-   N-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}-9H-purin-6-amine;-   N-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}propyl)-9H-purin-6-amine;-   (5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)methanol;-   2-(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)propan-2-ol;-   N-(1-[5-chloro-2-methoxy-3-[6-(1-methoxy-1-methylethyl)pyridin-3-yl]-4-methylphenyl]ethyl)-9H-purin-6-amine;-   3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;-   N-{1-[5-chloro-4-fluoro-2-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]ethyl}-9H-purin-6-amine    hydrochloride;-   N-{1-[5-chloro-4-fluoro-2-methoxy-3-(morpholin-4-ylmethyl)phenyl]ethyl}-9H-purin-6-amine;-   5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3-isopropyl-1,3-oxazolidin-2-one;-   1-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-2-morpholin-4-ylethanol;-   6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-4-isopropylmorpholin-3-one;-   4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one;-   4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methylpyrrolidin-2-one;-   N-{1-[4,5-dichloro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   N-{1-[3-(1-acetylazetidin-3-yl)-4,5-dichloro-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   2-(3-{2,3-dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)ethanol;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(tetrahydrofuran-3-yl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoro-1-methylethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-{1-[4,5-dichloro-2-methoxy-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(2-methoxyethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-(1-{4,5-dichloro-3-[1-(cyclopropylmethyl)azetidin-3-yl]-2-methoxyphenyl}ethyl)-9H-purin-6-amine;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(tetrahydro    furan-3-ylmethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(4,4,4-trifluorobutyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(1,3-thiazol-4-ylmethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(3,3,3-trifluoropropyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   (3-{2,3-dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)acetonitrile;-   N-(1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoro    ethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;-   2-(3-{2,3-dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)propan-1-ol;-   N-{1-[4,5-dichloro-3-(1-cyclobutylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;-   N-(1-{4,5-dichloro-3-[1-(2,2-difluoroethyl)azetidin-3-yl]-2-methoxyphenyl}ethyl)-9H-purin-6-amine;-   5-{3-cyano-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;-   4-ethoxy-2-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]-5-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;-   6-chloro-3-ethoxy-2-(1-ethylazetidin-3-yl)-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;    and-   6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;    or a pharmaceutically acceptable salt of any of the aforementioned.

In some embodiments for each of the aforementioned species, the compoundhas the (R)-configuration at the carbon atom in Formula I to which R¹ isattached.

In some embodiments for each of the aforementioned species, the compoundhas the (S)-configuration at the carbon atom in Formula I to which R¹ isattached.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)-includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

Throughout the definitions, the term “C_(n-m)” is referred to indicateC₁₋₄, C₁₋₆, and the like, wherein n and m are integers and indicate thenumber of carbons, wherein n-m indicates a range which includes theendpoints.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. In someembodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.Examples of alkyl moieties include, but are not limited to, chemicalgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl,3-pentyl, n-hexyl, 1,2,2-trimethylpropyl, and the like.

As used herein, the term “alkylene” refers to a divalent alkyl linkinggroup. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl, and the like.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. In someembodiments, the alkenyl moiety contains 2 to 6 or to 2 to 4 carbonatoms. Example alkenyl groups include, but are not limited to, ethenyl,n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6 or 2 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons.

Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxyand isopropoxy), t-butoxy, and the like. In some embodiments, the alkylgroup has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbonatoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂, wherein the alkyl group has n to m carbon atoms.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbonatoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4carbon atoms.

As used herein, the term “di C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbonatoms.

As used herein, the term “thio” refers to a group of formula —S—H.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(O)— group.

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkylamino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6 or 1 to 4 carbon atoms.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6 or 1 to 4 carbon atoms.

As used herein, the term “phenyl-C₁₋₄ alkyl” refers to a group offormula —C₁₋₄ alkylene-phenyl.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Ring-forming carbon atoms of a cycloalkyl group can beoptionally substituted by oxo or sulfido. Cycloalkyl groups also includecycloalkylidenes. Example cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl,cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl,norcarnyl, adamantyl, and the like. In some embodiments, cycloalkyl iscyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Also included inthe definition of cycloalkyl are moieties that have one or more aromaticrings fused (i.e., having a bond in common with) to the cycloalkyl ring,for example, benzo or thienyl derivatives of cyclopentane, cyclopentene,cyclohexane, and the like. A cycloalkyl group containing a fusedaromatic ring can be attached through any ring-forming atom including aring-forming atom of the fused aromatic ring.

As used herein, “5-6 membered heteroaryl” refers to a monocyclicaromatic heterocycle having at least one heteroatom ring member such assulfur, oxygen, or nitrogen and 5-6 ring members. In some embodiments,the heteroaryl ring has 1, 2, or 3 heteroatom ring members independentlyselected from nitrogen, sulfur and oxygen. In some embodiments, theheteroaryl ring has 1, 2, 3 or 4 N heteroatom ring members. In someembodiments, any ring-forming N in a heteroaryl moiety can be anN-oxide.

A five-membered ring heteroaryl is a heteroaryl with a ring having fivering atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary five-membered ringheteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl,oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl,tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl.

A six-membered ring heteroaryl is a heteroaryl with a ring having sixring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms areindependently selected from N, O, and S. Exemplary six-membered ringheteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl andpyridazinyl.

As used herein, the term “heteroarylalkyl” refers to a group of formula-alkylene-heteroaryl. In some embodiments, heteroarylalkyl is 5-6membered heteroaryl ring, wherein the heteroaryl ring is monocyclic andhas 1, 2, or 3 heteroatom ring members independently selected fromnitrogen, sulfur and oxygen.

As used herein, “4-7 membered heterocycloalkyl” refers to non-aromaticheterocycles having one or more ring-forming heteroatoms selected fromO, N, or S and having 4-7 ring members. Heterocycloalkyl groups includespirocycles. Example “4-7 membered heterocycloalkyl” groups includepyrrolidin2-one, 1,3-isoxazolidin-2-one, pyranyl, azetidinyl,morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl,tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl,isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl,imidazolidinyl, azepanyl, and the like. Ring-forming carbon atoms andheteroatoms of a heterocycloalkyl group can be optionally substituted byoxo or sulfido (e.g., C(O), S(O), C(S), or S(O)₂, etc.). Theheterocycloalkyl group can be attached through a ring-forming carbonatom or a ring-forming heteroatom. In some embodiments, theheterocycloalkyl group contains 0 to 3 double or triple bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double bonds.

As used herein, the term “heterocycloalkylalkyl” refers to a group offormula alkylene-heterocycloalkyl. In some embodiments,heterocycloalkylalkyl is 4-7 membered heterocycloalkyl ring, wherein theheterocycloalkyl portion is monocyclic and has 1, 2, or 3 heteroatomring members independently selected from nitrogen, sulfur and oxygen.

As used herein, the term “cyano-C₁₋₆ alkyl” refers to a group of formula—C₁₋₆ alkylene-CN.

As used herein, the term “HO—C₁₋₆ alkyl” refers to a group of formula—C₁₋₆ alkylene-OH.

As used herein, the term “C₁₋₄ alkoxy-C₁₋₆ alkyl” refers to a group offormula —C₁₋₆ alkylene-(C₁₋₄ alkoxy).

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds, and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

In some embodiments, the compound has the (R)-configuration at thecarbon attached to R¹. In some embodiments, the compound has the(S)-configuration at the carbon attached to R¹.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such as3-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. For example, purine includes the 9H and a 7H tautomericforms:

Compounds of the invention can include both the 9H and 7H tautomericforms.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric iosomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds of theinvention. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds of the invention, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g. a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present invention can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (ACN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977), each of which is incorporated herein by reference in itsentirety.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999), which is incorporated herein by referencein its entirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS) or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) (“Preparative LC-MSPurification: Improved Compound Specific Method Optimization” Karl F.Blom, Brian Glass, Richard Sparks, Andrew P. Combs J Combi. Chem. 2004,6(6), 874-883, which is incorporated herein by reference in itsentirety) and normal phase silica chromatography.

Compounds of Formula I can be formed as shown in Scheme I. The compound(i) can be halogenated with N-chlorosuccinamide, N-bromosuccinamide orN-iodosuccinamide to give compound (ii) where X═Cl, Br, or I. The halogroup of (ii) can be coupled to R³-M, where M is a boronic acid, boronicester or an appropriately substituted metal (e.g., R³-M is R³—B(OH)₂ orR³—Sn(Bu)₄), under standard Suzuki conditions or standard Stilleconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base) to give a derivative of formula (iii). Alternatively,R³-M can be a cyclic amine (where M is H and attached to the aminenitrogen) with coupling to compound (ii) being performed by heating inbase or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to afford ketone (iii). Reductiveamination of the ketone (iii) can furnish the amine intermediate (v).Alternatively, ketone (iii) can be reduced to give an alcohol which canbe converted to the mesylate and reacted with sodium azide to give anazide derivative (iv). The azide of compound (iv) can be converted to anamine (v) under appropriate reducing conditions, such astrimethylphosphine or TMSI. The amine (v) can be reacted with anappropriate alkylating agent R^(A)X (e.g., MeI) or reacted underreductive amination conditions to give compound (vi). Finally compound(vi) can be reacted with a heteroaryl halide compound (e.g., Ar—X) togive a compound of Formula I. The reaction of amine (v) with R^(A)—X canbe eliminated to give compounds of Formula I, wherein R^(A) is H.

Alternatively, compounds of Formula I can also be formed as shown inScheme II. The ketone compound (i) can be halogenated withN-chlorosuccinamide, N-bromosuccinamide or N-iodosuccinamide to givecompound (ii) where X═Cl, Br, or I. Ketone (ii) can be reduced to givean alcohol (iii) which can be converted to the mesylate and reacted withsodium azide to give an azide derivative (iv). The azide of compound(iv) can be converted to an amine (v) under appropriate reducingconditions, such as trimethylphosphine or TMSI. The amine (v) can beprotected with a suitable protecting group (e.g., by reacting withBoc₂O) and purified by chiral chromatography to afford a singleenantiomer of amine compound (v). The amino group can be deprotected(e.g., TFA when P=Boc) and reacted with an appropriate alkylating agentR^(A)X (e.g., MeI) and the resulting secondary amine can be reacted witha heteroaryl halide compound (e.g., Ar—X) to give a compound (vi). Thereaction of amine (v) with R^(A)—X can be eliminated to give compounds(vi), wherein R^(A) is H. Finally, the halo group of (vi) can be coupledto R³-M, where M is a boronic acid, boronic ester or an appropriatelysubstituted metal (e.g., R³-M is R³—B(OH)₂ or R³—Sn(Bu)₄), understandard Suzuki conditions or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base)) to give a derivative of formula (vii).Alternatively, R³-M can be a cyclic amine (where M is H and attached tothe amine nitrogen) with coupling to compound (vi) being performed byheating in base or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to afford compounds of Formula I(vii).

Compounds of Formula I, wherein L is O, N, or S, can be formed as shownin Scheme III. The thiols, phenols or amines (i) can be alkylated usingMitsunobu conditions (e.g., R′OH, DEAD, Ph₃P) or standard alkylatingconditions (R′-Lg, Lg=leaving group) to afford thioether, ether, oralkylamine derivatives (ii), respectively. The halo group (e.g., X═Br,I) of (ii) can be coupled to R³-M, where M is a boronic acid, boronicester or an appropriately substituted metal (e.g., R³-M is R³—B(OH)₂ orR³—Sn(Bu)₄), under standard Suzuki conditions or standard Stilleconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)-palladium(0) and a base (e.g., abicarbonate or carbonate base)) to give a derivative of formula (iii).Alternatively, R³-M can be a cyclic amine (where M is H and attached tothe amine nitrogen) with coupling to compound (ii) being performed byheating in base or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)-palladium(0)and a base (e.g., an alkoxide base)) to afford compounds of formula(iii). The ketone (iii) can be transformed using similar methods asshown in Scheme I and II to afford compounds of Formula I (iv).Alternatively, the halo-ketone (ii) can be transformed using similarmethods as shown in Scheme I and II to afford halo intermediate (v).Suzuki, Stille, Negishi or Buchwald coupling of R³-M with halointermediate (v) by similar methods described in Schemes I and II canalso afford compounds of Formula I (iv).

Compounds of Formula I can be formed as shown in Scheme IV. Compound (i)can be acylated with a suitable acylating reagent (e.g., R¹—COCl) toform an ester which can be rearranged under Lewis acid conditions e.g.,BF₃/HOAc complex) to afford ketone (ii). Halogenation of ketone (ii)using NXS (e.g., NXS=N-chlorosuccinamide, N-bromosuccinamide orN-iodosuccinamide) can give compound (iii) where X═Cl, Br, or I. Thephenol can be converted to the triflate (iv) using standard conditions(e.g., Tf₂O). The triflate group of (iv) can be coupled to R²-M, where Mis a boronic acid, boronic ester or an appropriately substituted metal(e.g., R²-M is R²—B(OH)₂ or R²—Sn(Bu)₄), under standard Suzukiconditions or standard Stille conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., a bicarbonate or carbonate base)) to give a derivativeof formula (v). Alternatively, R²-M can be a cyclic amine (where M is Hand attached to the amine nitrogen) with coupling to compound (iv) beingperformed by heating in base or under Buchwald conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., an alkoxidebase)) to afford ketone (v). The halo group of (v) can be coupled toR³-M, where M is a boronic acid, boronic ester or an appropriatelysubstituted metal (e.g., R³-M is R³—B(OH)₂ or R³—Sn(Bu)₄), understandard Suzuki conditions or standard Stille conditions (e.g., in thepresence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base)) to give a derivative of formula (vi). Alternatively,R³-M can be a cyclic amine (where M is H and attached to the aminenitrogen) with coupling to compound (iv) being performed by heating inbase or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to afford ketone (vi). The ketone(vi) can be transformed using similar methods as shown in Scheme I andII to afford compounds of Formula I (viii).

Alternatively, the halo-ketone (v) can be transformed using similarmethods as shown in Scheme I and II to afford halo intermediate (viii).Suzuki, Stille, Negishi or Buchwald coupling of M-R³ with compound(viii) by similar methods described in Schemes I and II can also affordcompounds of Formula I (vii).

Ketones which can be used in the processes of Scheme I, II and III canbe formed as shown in Scheme V below. The carboxylic acid (i) can beactivated with a coupling agent (e.g., HBTU, HATU or EDC) and thenreacted with N,O-dimethylhydroxylamine to give aN-methoxy-N-methylcarboxamide derivative (ii). Amide (ii) may then bereacted with a Grignard reagent of formula R¹—MgX (X=halo) to give aketone (iii). The ketone (iii) can be transformed using similar methodsas shown in Scheme I, II and III to afford compounds of Formula I.

Ketones which can be used in the processes of Scheme I, II and III, canalso be formed as shown in Scheme VI below. The carboxylic acid (i) canbe activated with a coupling agent (e.g. HBTU or HATU) and then reactedwith N,O-dimethylhydroxylamine to give a N-methoxy-N-methylcarboxamide.The thiols, phenols or amines can be alkylated using Mitsunobuconditions (e.g., R′OH, DEAD, Ph₃P) or standard alkylating conditions(R′-Lg, Lg=leaving group) to afford thioether, ether or alkylaminederivatives (ii), respectively. The halo group (e.g., X═Br, or I) of(ii) can be coupled to R³-M, where M is a boronic acid, boronic ester oran appropriately substituted metal (e.g., R³-M is R³—B(OH)₂ orR³—Sn(Bu)₄), under standard Suzuki conditions or standard Stilleconditions (e.g., in the presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0) and a base (e.g., a bicarbonateor carbonate base)) to give a derivative of formula (iii).Alternatively, R³-M can be a cyclic amine (where M is H and attached tothe amine nitrogen) with coupling to compound (ii) being performed byheating in base or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to afford amides (iii) of FormulaI. Reaction of compound (iii) with a Grignard reagent of formula R¹—MgX(X=halo) can give ketone (iv). The ketone (iv) can be transformed usingsimilar methods as shown in Scheme I, II and III to afford compounds ofFormula I.

Compounds which can be used in the processes of Schemes I-III can alsobe formed as shown in Scheme VII. The halo-ketone (i) can be convertedto the cyano-ketone (ii) using standard cyanation conditions (e.g.,Pd(0) and Zn(CN)₂). Hydrolysis of the cyano group of (ii) under acid orbase conditions can give the carboxylic acid which can be coupled toamines using a coupling agent (e.g., HATU, HBTU, EDC) and appropriateamines (HNR^(c)R^(d)) to give amide (iii). In some embodiments, R^(c)and R^(d), along with the nitrogen atom to which they are attached canoptionally cyclize to form a 4-7 membered heterocycloalkyl group(thereby providing compounds wherein R³ is C(O)R^(b), wherein R^(b) is4-7 membered heterocycloalkyl). The ketone of amide (iii) can betransformed using similar methods as shown in Scheme I, II and III toafford compounds of Formula I.

Additional compounds which can be used in the processes of Schemes I-IIIcan be formed as shown in Scheme VIII. The ketone (i) can be convertedto the nitro-ketone (ii) using standard nitration conditions (e.g.,HNO₃). Reduction of the nitro group of (ii) under standard conditions(e.g., Fe, Zn, H₂ over Pd/C) can give the amino compound which can beacylated with appropriate acylating agents (e.g., R^(c)C═OCl, ROC═OCl,SO₂Cl, RRNC═O) to give ketone (iii). The ketone (iii) can be transformedusing similar methods as shown in Scheme I, II and III to affordcompounds of Formula I. In some embodiments, R^(c) and R^(d), along withthe nitrogen atom to which they are attached can optionally cyclize toform a 4-7 membered heterocycloalkyl group (thereby providing compoundswherein R³ is C(O)R^(b), wherein R^(b) is 4-7 memberedheterocycloalkyl).

Further compounds which can be used in the processes of Schemes I-IIIcan be formed as shown in Scheme IX. The ether (i) can be converted to aphenol (ii) using standard nitration conditions (e.g., BBr₃). Thehalo-phenol (ii) can be converted to the cyano-phenol (iii) usingstandard cyanation conditions (e.g., CuCN or Pd(0) and Zn(CN)₂). Thephenol (iii) can be converted to the triflate (iv) using Tf₂O. Thetriflate group of (iv) can be coupled to R²-M, where M is a boronicacid, boronic ester or an appropriately substituted metal (e.g., R²-M isR²—B(OH)₂ or R²—Sn(Bu)₄), under standard Suzuki conditions or standardStille conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base (e.g., abicarbonate or carbonate base)) to give a derivative of formula (v).Alternatively, R²-M can be a cyclic amine (where M is H and attached tothe amine nitrogen) with coupling to compound (iv) being performed byheating in base or under Buchwald conditions (e.g., in the presence of apalladium(0) catalyst, such as tetrakis(triphenylphosphine)palladium(0)and a base (e.g., an alkoxide base)) to afford ketone (v). Hydrolysis ofthe cyano group of (v) under acid or base conditions can give thecarboxylic acid which can be coupled to amines using a coupling agent(e.g., HATU, HBTU, EDC) and an appropriate amine (HNR₁R₂) to give amide(vi). The ketone of amide (vi) can be transformed using similar methodsas shown in Scheme I, II and III to afford compounds of Formula I.

Compounds of Formula I can be formed as shown in Scheme X. The halo (X¹)group of (i) can be coupled to R³-M, where M is an appropriatelysubstituted metal (e.g., R³-M is Zn(R³)₂); appropriate non-limitingstarting materials for generating R³-M are shown in Scheme X) understandard Negishi conditions (e.g., in the presence of a palladium(0)catalyst, such as Pd₂(dba)₃ or tetrakis(triphenylphosphine)palladium(0))to give a protected amino derivative of formula (II). The nitrogenprotecting group Pg in formula (II) (e.g., Boc or Cbz) can be removedunder a variety of standard conditions (e.g., TFA or HCl for Boc and H₂over Pd/C for Cbz) to afford the free amine which can be further reactedwith a variety of alkylating, arylating, acylating, or sulfonylatingconditions (e.g., R^(3a)—X²; where X²=halo or other leaving group andR^(3a)=alkyl, aryl, acyl, sulfonyl and a base, such as TEA) to givecompounds of formula (iii). Compounds of formula (iii) can be convertedto compounds of Formula I using conditions described in Scheme I.

Alternatively, compounds of Formula I can be formed as shown in SchemeXa wherein the protected amino derivative (ii) can be reduced to thealcohol which can be converted to a leaving group (e.g., Lg=mesylate orhalo, such as Cl or bromo) to give compounds of formula (Iv). Theleaving group of compound (iv) can be displaced with sodium azide toafford the azide derivative which can be reduced (e.g.,trimethylphosphine or H₂ over Pd/C) to give the corresponding aminoderivative (v). Purination of the amino derivative under standardconditions and subsequent removal of the nitrogen protecting group(e.g., Boc or Cbz) under a variety of standard conditions (e.g., TFA orHCl for Boc and H₂ over Pd/C for Cbz) can afford the free amine whichcan be further reacted under a variety of alkylating, arylating,acylating, sulfonylating conditions (e.g., R^(3a)—X¹; where X¹=halo andR^(3a)=alkyl, aryl, acyl, sulfonyl and a base, such as TEA) to givecompounds of formula (vii). Removal of the purine protecting group, whenpresent, can give compounds of Formula I.

Compounds of Formula I can be formed as shown in Scheme X¹. The halogroup, X¹, of (i) can be coupled to an alkene (e.g., acrylate oracrylamide) under standard Heck conditions (e.g., in the presence of apalladium(II) catalyst, such as palladium acetate)) to give an alkene offormula (II). Reaction of alkene (ii) with nitromethane in the presenceof DBU can afford the nitro derivative (iii) which can be reduced understandard conditions (e.g., NiCl₂/NaBH₄) to give the free amine thatcloses to form the lactam (iv). The lactam can be alkylated understandard conditions (R^(3a)—X²; X²=halo in the presence of a base, suchas TEA or NaH) to give an N-alkyl-lactam (v). Compounds of formula (v)and pyrrolidines derived from the reduction of the lactam (v) withsuitable reducing agents, such as LiAlH₄, can be converted to compoundsof Formula I using conditions described in Scheme I.

Compounds of Formula I can be formed as shown in Scheme XII. The halogroup X¹ of (i) can be coupled to R³-M, where M is an appropriatelysubstituted metal (e.g., R³-M is R³B(OH)₂; appropriate non-limitingstarting materials for generating R³-M are shown in Scheme XII) understandard Suzuki conditions (e.g., in the presence of a palladium(0)catalyst, such as tetrakis(triphenylphosphine)palladium(0)) to give analkene of formula (II). Epoxidation of alkene (ii) with mCPBA can affordthe epoxide (iii) which can be reacted with a secondary or primary amine(amine=NHR^(c)R^(d); R^(c)═H for primary amine) to give amino compoundsof formula (Iv). Secondary or tertiary amine derivatives (iv) can befurther reacted with carbonyldiamidazole or phosgene to form anoxazolidinone (v) or an acetyl-halide (e.g., chloro-acetylchloride inthe presence of base, such as TEA) to give the N-acyl derivative whichcan be converted to the morpholinone derivative (vi) upon treatment witha base (e.g., NaH). Compounds of formula (Iv, v, and yl) can bedeprotected using standard conditions (e.g., Pg=THP then treat with anacid, such as TFA or HCl) to give compounds of Formula I.

Compounds of Formula I can be synthesized as shown in Scheme XIII. Thehalo group (e.g., X¹═Cl, Br, I) of (i) can be converted to the boronicester (ii) under standard conditions (e.g., pinnacle boronate ester inthe presence of a palladium(0) catalyst, such astetrakis(triphenylphosphine)palladium(0)) The boronate (ii) can bereacted with an arylhalide or heteroarylhalide (e.g., R³—X²) underSuzuki conditions (e.g., in the presence of a palladium(0) catalyst,such as tetrakis(triphenylphosphine)palladium(0) and a base, such asNa₂CO₃) to give compounds of formula (iii). Compounds of formula (iii)can be converted to compounds of Formula I using conditions described inScheme I.

Methods

The compounds of the invention can modulate activity of one or more ofvarious kinases including, for example, phosphoinositide 3-kinases(PI3Ks). The term “modulate” is meant to refer to an ability to increaseor decrease the activity of one or more members of the PI3K family.Accordingly, the compounds of the invention can be used in methods ofmodulating a PI3K by contacting the PI3K with any one or more of thecompounds or compositions described herein. In some embodiments,compounds of the present invention can act as inhibitors of one or morePI3Ks. In further embodiments, the compounds of the invention can beused to modulate activity of a PI3K in an individual in need ofmodulation of the receptor by administering a modulating amount of acompound of the invention, or a pharmaceutically acceptable saltthereof. In some embodiments, modulating is inhibiting.

Given that cancer cell growth and survival is impacted by multiplesignaling pathways, the present invention is useful for treating diseasestates characterized by drug resistant kinase mutants. In addition,different kinase inhibitors, exhibiting different preferences in thekinases which they modulate the activities of, may be used incombination. This approach could prove highly efficient in treatingdisease states by targeting multiple signaling pathways, reduce thelikelihood of drug-resistance arising in a cell, and reduce the toxicityof treatments for disease.

Kinases to which the present compounds bind and/or modulate (e.g.,inhibit) include any member of the PI3K family. In some embodiments, thePI3K is PI3Kα, PI3Kγ, or PI3Kδ. In some embodiments, the PI3K is PI3Kγor PI3Kδ. In some embodiments, the PI3K is PI3Kγ. In some embodiments,the PI3K is PI3Kδ. In some embodiments, the PI3K includes a mutation. Amutation can be a replacement of one amino acid for another, or adeletion of one or more amino acids. In such embodiments, the mutationcan be present in the kinase domain of the PI3K.

In some embodiments, more than one compound of the invention is used toinhibit the activity of one kinase (e.g., PI3Kγ or PI3Kδ).

In some embodiments, more than one compound of the invention is used toinhibit more than one kinase, such as at least two kinases (e.g., PI3Kγand PI3Kδ).

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activity of one kinase(e.g., PI3Kγ or PI3Kδ).

In some embodiments, one or more of the compounds is used in combinationwith another kinase inhibitor to inhibit the activities of more than onekinase (e.g., PI3Kγ or PI3Kδ), such as at least two kinases.

The compounds of the invention can be selective. By “selective” is meantthat the compound binds to or inhibits a kinase with greater affinity orpotency, respectively, compared to at least one other kinase. In someembodiments, the compounds of the invention are selective inhibitors ofPI3Kγ or PI3Kδ over PI3Kα and/or PI3Kβ. In some embodiments, thecompounds of the invention are selective inhibitors of PI3Kδ (e.g., overPI3Kα, PI3β and PI3Kγ). In some embodiments, the compounds of theinvention are selective inhibitors of PI3Kγ (e.g., over PI3Kα, PI3Kβ andPI3Kδ). In some embodiments, selectivity can be at least about 2-fold,5-fold, 10-fold, at least about 20-fold, at least about 50-fold, atleast about 100-fold, at least about 200-fold, at least about 500-foldor at least about 1000-fold. Selectivity can be measured by methodsroutine in the art. In some embodiments, selectivity can be tested atthe K_(m) ATP concentration of each enzyme. In some embodiments, theselectivity of compounds of the invention can be determined by cellularassays associated with particular PI3K kinase activity.

Another aspect of the present invention pertains to methods of treatinga kinase (such as PI3K)-associated disease or disorder in an individual(e.g., patient) by administering to the individual in need of suchtreatment a therapeutically effective amount or dose of one or morecompounds of the present invention or a pharmaceutical compositionthereof. A PI3K-associated disease can include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the PI3K, including overexpression and/or abnormal activitylevels. In some embodiments, the disease can be linked to Akt (proteinkinase B), mammalian target of rapamycin (mTOR), orphosphoinositide-dependent kinase 1 (PDK1). In some embodiments, themTOR-related disease can be inflammation, atherosclerosis, psoriasis,restenosis, benign prostatic hypertrophy, bone disorders, pancreatitis,angiogenesis, diabetic retinopathy, atherosclerosis, arthritis,immunological disorders, kidney disease, or cancer. A PI3K-associateddisease can also include any disease, disorder or condition that can beprevented, ameliorated, or cured by modulating PI3K activity. In someembodiments, the disease is characterized by the abnormal activity ofPI3K. In some embodiments, the disease is characterized by mutant PI3K.In such embodiments, the mutation can be present in the kinase domain ofthe PI3K.

Examples of PI3K-associated diseases include immune-based diseasesinvolving the system including, for example, rheumatoid arthritis,allergy, asthma, glomerulonephritis, lupus, or inflammation related toany of the above.

Further examples of PI3K-associated diseases include cancers such asbreast, prostate, colon, endometrial, brain, bladder, skin, uterus,ovary, lung, pancreatic, renal, gastric, or hematological cancer.

In some embodiments, the hematological cancer is acute myeloblasticleukemia (AML) or chronic myeloid leukemia (CML), or B cell lymphoma.

Further examples of PI3K-associated diseases include lung diseases suchas acute lung injury (ALI) and adult respiratory distress syndrome(ARDS).

Further examples of PI3K-associated diseases include osteoarthritis,restenosis, atherosclerosis, bone disorders, arthritis, diabeticretinopathy, psoriasis, benign prostatic hypertrophy, inflammation,angiogenesis, pancreatitis, kidney disease, inflammatory bowel disease,myasthenia gravis, multiple sclerosis, or Sjögren's syndrome, and thelike.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” a PI3K with a compound of the invention includesthe administration of a compound of the present invention to anindividual or patient, such as a human, having a PI3K, as well as, forexample, introducing a compound of the invention into a samplecontaining a cellular or purified preparation containing the PI3K.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician. In some embodiments, the dosage ofthe compound, or a pharmaceutically acceptable salt thereof,administered to a patient or individual is about 1 mg to about 2 g, orabout 50 mg to about 500 mg.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology); and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease.

Combination Therapies

One or more additional pharmaceutical agents such as, for example,chemotherapeutics, anti-inflammatory agents, steroids,immunosuppressants, as well as Bcr-Abl, Flt-3, EGFR, HER2, JAK, c-MET,VEGFR, PDGFR, cKit, IGF-1R, RAF and FAK kinase inhibitors such as, forexample, those described in WO 2006/056399, or other agents such as,therapeutic antibodies can be used in combination with the compounds ofthe present invention for treatment of PI3K-associated diseases,disorders or conditions. The one or more additional pharmaceuticalagents can be administered to a patient simultaneously or sequentially.

Example antibodies for use in combination therapy include but are notlimited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A),Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g.anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) andantibodies directed to c-MET.

One or more of the following agents may be used in combination with thecompounds of the present invention and are presented as a non limitinglist: a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol,etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel,epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide,cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa,Tarceva, antibodies to EGFR, Gleevec™ intron, ara-C, adriamycin,cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin,ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin,Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin,Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone,Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone,Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide,Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide,Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene,Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine,Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin,Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa,Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,Fulvestrant, Ifosfomide, Rituximab, C225, Campath, Clofarabine,cladribine, aphidicolon, rituxan, sunitinib, dasatinib, tezacitabine,Sml1, fludarabine, pentostatin, triapine, didox, trimidox, amidox, 3-AP,MDL-101,731, and bendamustine (Treanda).

Example chemotherapeutics include proteosome inhibitors (e.g.,bortezomib), thalidomide, revlimid, and DNA-damaging agents such asmelphalan, doxorubicin, cyclophosphamide, vincristine, etoposide,carmustine, and the like.

Example steroids include coriticosteroids such as dexamethasone orprednisone.

Example Bcr-Abl inhibitors include the compounds, and pharmaceuticallyacceptable salts thereof, of the genera and species disclosed in U.S.Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No, 60/578,491.

Example suitable Flt-3 inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 03/037347, WO03/099771, and WO 04/046120.

Example suitable RAF inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 00/09495 and WO05/028444.

Example suitable FAK inhibitors include compounds, and theirpharmaceutically acceptable salts, as disclosed in WO 04/080980, WO04/056786, WO 03/024967, WO 01/064655, WO 00/053595, and WO 01/014402.

In some embodiments, the compounds of the invention can be used incombination with one or more other kinase inhibitors including imatinib,particularly for treating patients resistant to imatinib or other kinaseinhibitors.

In some embodiments, the compounds of the invention can be used incombination with a chemotherapeutic in the treatment of cancer, such asmultiple myeloma, and may improve the treatment response as compared tothe response to the chemotherapeutic agent alone, without exacerbationof its toxic effects. Examples of additional pharmaceutical agents usedin the treatment of multiple myeloma, for example, can include, withoutlimitation, melphalan, melphalan plus prednisone [MP], doxorubicin,dexamethasone, and Velcade (bortezomib). Further additional agents usedin the treatment of multiple myeloma include Bcr-Abl, Flt-3, RAF and FAKkinase inhibitors. Additive or synergistic effects are desirableoutcomes of combining a PI3K inhibitor of the present invention with anadditional agent. Furthermore, resistance of multiple myeloma cells toagents such as dexamethasone may be reversible upon treatment with thePI3K inhibitor of the present invention. The agents can be combined withthe present compound in a single or continuous dosage form, or theagents can be administered simultaneously or sequentially as separatedosage forms.

In some embodiments, a corticosteroid such as dexamethasone isadministered to a patient in combination with the compounds of theinvention where the dexamethasone is administered intermittently asopposed to continuously.

In some further embodiments, combinations of the compounds of theinvention with other therapeutic agents can be administered to a patientprior to, during, and/or after a bone marrow transplant or stem celltransplant.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of the invention can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the invention or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers (excipients). In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, for example, a capsule, sachet,paper, or other container. When the excipient serves as a diluent, itcan be a solid, semi-solid, or liquid material, which acts as a vehicle,carrier or medium for the active ingredient. Thus, the compositions canbe in the form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, for example, up to 10% byweight of the active compound, soft and hard gelatin capsules,suppositories, sterile injectable solutions, and sterile packagedpowders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art, e.g., see International App. No.WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compositions of the invention contain fromabout 5 to about 50 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 5 to about 10, about 10 to about 15, about 15 to about20, about 20 to about 25, about 25 to about 30, about 30 to about 35,about 35 to about 40, about 40 to about 45, or about 45 to about 50 mgof the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 50 to about 500 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 50 to about 100, about 100 to about 150, about 150 toabout 200, about 200 to about 250, about 250 to about 300, about 350 toabout 400, or about 450 to about 500 mg of the active ingredient.

In some embodiments, the compositions of the invention contain fromabout 500 to about 1000 mg of the active ingredient. One having ordinaryskill in the art will appreciate that this embodies compositionscontaining about 500 to about 550, about 550 to about 600, about 600 toabout 650, about 650 to about 700, about 700 to about 750, about 750 toabout 800, about 800 to about 850, about 850 to about 900, about 900 toabout 950, or about 950 to about 1000 mg of the active ingredient.

Similar dosages may be used of the compounds described herein in themethods and uses of the invention.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, for example, liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, for example,glycerol, hydroxyethyl cellulose, and the like. In some embodiments,topical formulations contain at least about 0.1, at least about 0.25, atleast about 0.5, at least about 1, at least about 2, or at least about 5wt % of the compound of the invention. The topical formulations can besuitably packaged in tubes of, for example, 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, for example, the particular use for which the treatment ismade, the manner of administration of the compound, the health andcondition of the patient, and the judgment of the prescribing physician.The proportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

The compositions of the invention can further include one or moreadditional pharmaceutical agents such as a chemotherapeutic, steroid,anti-inflammatory compound, or immunosuppressant, examples of which arelisted herein.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to labeled compounds ofthe invention (radio-labeled, fluorescent-labeled, etc.) that would beuseful not only in imaging techniques but also in assays, both in vitroand in vivo, for localizing and quantitating PI3K in tissue samples,including human, and for identifying PI3K ligands by inhibition bindingof a labeled compound. Accordingly, the present invention includes PI3Kassays that contain such labeled compounds.

The present invention further includes isotopically-labeled compounds ofthe invention. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited to ³H(also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. Theradionuclide that is incorporated in the instant radio-labeled compoundswill depend on the specific application of that radio-labeled compound.For example, for in vitro PI3K labeling and competition assays,compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, 131I, ³⁵S or willgenerally be most useful. For radio-imaging applications 11C, ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of3H, ¹C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, one or more H atoms forany compound described herein is each replaced by a deuterium atom.

The present invention can further include synthetic methods forincorporating radio-isotopes into compounds of the invention. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of invention.

A labeled compound of the invention can be used in a screening assay toidentify/evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a PI3K by monitoring its concentrationvariation when contacting with the PI3K, through tracking of thelabeling. For example, a test compound (labeled) can be evaluated forits ability to reduce binding of another compound which is known to bindto a PI3K (i.e., standard compound). Accordingly, the ability of a testcompound to compete with the standard compound for binding to the PI3Kdirectly correlates to its binding affinity. Conversely, in some otherscreening assays, the standard compound is labeled and test compoundsare unlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of PI3K-associated diseases ordisorders, such as cancer, which include one or more containerscontaining a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention. Such kits can furtherinclude, if desired, one or more of various conventional pharmaceuticalkit components, such as, for example, containers with one or morepharmaceutically acceptable carriers, additional containers, etc., aswill be readily apparent to those skilled in the art. Instructions,either as inserts or as labels, indicating quantities of the componentsto be administered, guidelines for administration, and/or guidelines formixing the components, can also be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to be PI3Kinhibitors according to at least one assay described herein.

EXAMPLES

The example compounds below containing one or more chiral centers wereobtained in racemate form or as isomeric mixtures, unless otherwisespecified. At points throughout the Examples, the stereochemistry at thecarbon attached to R¹ has been indicated, as currently understood.

Example 14-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile

Step 1. 1-(3-Bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone

To a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone(1.0 g, 3.6 mmol) in methylene chloride (20 mL) was added 1.0 M borontribromide in methylene chloride (3.8 mL, 3.8 mmol) at −78° C. Afterstirring at −78° C. for 10 minutes, the reaction was allowed to warm to0° C. and was then quenched with water at 0° C. and extracted withdichloromethane. The combined organic layers were washed with brine anddried over sodium sulfate. The volatiles were removed under reducedpressure to afford 1-(3-Bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone(0.91 g, 96%). ¹H NMR (CDCl₃, 300 MHz) δ 12.96 (1H, s), 7.72 (1H, s),2.64 (3H, s), 2.59 (3H, s) ppm.

Step 2. 3-Acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile

A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (4.9g, 18 mmol) and copper cyanide (2.5 g, 28 mmol) in N-methylpyrrolidinone(15 mL) was heated at 200° C. for 1 hour. The resulting mixture wasallowed to cool to room temperature and was then diluted with ethylacetate and 1 N HCl. The organic and aqueous layers were separated andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with water and brine, dried over magnesium sulfateand concentrated to dryness under reduced pressure to give3-Acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile (3.7 g, 96%). LCMScalculated for C₁₀H₉ClNO₂ (M+H)⁺: m/z=210.0. found: 210.1.

Step 3. 6-Acetyl-4-chloro-2-cyano-3-methylphenyltrifluoromethanesulfonate

To a mixture of 3-acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile (3.7 g,18 mmol) in methylene chloride (70 mL) was added triethylamine (7.4 mL,53 mmol) and trifluoromethanesulfonic anhydride (4.4 mL, 26 mmol) at−78° C. The reaction mixture was allowed to warm to room temperaturegradually and then stirred at room temperature for 30 minutes. Themixture was quenched with water and extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated to dryness. The resulting residue was purifiedon silica gel, eluting with 0 to 40% ethyl acetate in hexane, to givethe desired product (2.54 g, 42% isolated yield for 3 steps). LCMScalculated for C₁₁H₈ClF₃NO₄S (M+H)⁺: =342.0. found: 342.1.

Step 4. 6-Acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile

A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyltrifluoromethanesulfonate (2.54 g, 7.4 mmol) and (3-fluorophenyl)boronicacid (1.6 g, 11 mmol) in toluene (70 mL) and saturated sodiumbicarbonate (70 mL) was bubbled with N₂ to degas. Aftertetrakis(triphenylphosphine)palladium(0) (0.43 g, 0.37 mmol) was added,the mixture was bubbled with N₂ for 5 min more and then heated at 80° C.for 2 hours. After cool to room temperature, the mixture was dilutedwith ethyl acetate. The layers were separated and the aq. layer wasextracted with more ethyl acetate. The combined extracts were washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The residuewas purified on silica gel column, eluting with 0 to 40% ethyl acetatein hexane, to give the desired product (2.1 g, 99%). LCMS calculated forC₁₆H₁₂ClFNO (M+H)⁺: m/z=288.1. found: 288.1.

Step 5.6-(1-Aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile

A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile(50 mg, 0.2 mmol) and ammonium acetate (130 mg, 1.7 mmol) in methanol(0.98 mL) and acetonitrile (0.99 mL) was heated at 65° C. in a sealedtube for 30 min. After the mixture was cooled, sodium cyanoborohydride(22 mg, 0.35 mmol) was added. The reaction was heated at 65° C. foranother 4 hours, then cooled to room temperature and quenched withsaturated sodium bicarbonate and extracted with dichloromethane. Thecombined extracts were dried over magnesium sulfate and evaporated todryness. The residue was used directly in next step. LCMS calculated forC₁₆H₁₅ClFN₂ (M+H)⁺: m/z=289.1. found: 289.1.

Step 6.4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile

A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol),6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (50mg, 0.2 mmol), and N,N-diisopropylethylamine (0.060 mL, 0.35 mmol) inisopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₁H₁₇ClFN₆(M+H)⁺: m/z=407.1. found: 407.1.

Example 24-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide

Step 1. 6-Acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide

A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile(0.87 g, 3.0 mmol) and potassium hydroxide (0.34 g, 6.1 mmol) in ethanol(4 mL) was refluxed for 2 hours. The mixture was cooled, acidified with1 N HCl, and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over magnesium sulfate, and evaporated todryness under reduced pressure to yield the crude product. LCMScalculated for C₁₆H₁₄ClFNO₂ (M+H)⁺: m/z=306.1. found: 306.0.

Step 2.6-(1-Aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide

A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide(110 mg, 0.34 mmol) and ammonium acetate (270 mg, 3.4 mmol) in methanol(1.9 mL) and acetonitrile (2.0 mL) was heated at 65° C. in a sealed tubefor 30 min. The mixture was cooled and sodium cyanoborohydride (43 mg,0.69 mmol) was added. The reaction was heated at 65° C. for another 4hours. The mixture was cooled, quenched with saturated sodiumbicarbonate, and extracted with dichloromethane. The combined extractswere dried over magnesium sulfate and evaporated to dryness. The residuewas used directly in next step (98 mg, 93%). LCMS calculated forC₁₆H₁₇ClFN₂O (M+H)⁺: m/z=307.1. found: 306.9.

Step 3.4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide

A mixture of 6-bromo-9H-purine (110 mg, 0.56 mmol),6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide(0.086 g, 0.28 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol)in isopropyl alcohol (2 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product (49 mg, 41%). LCMS calculated forC₂₁H₁₉ClFN₆O (M+H)⁺: m/z=425.1. found: 425.0.

Example 3N-[1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethyl]-9H-purin-6-amine

Step 1. 1-(5-Chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone

To a mixture of 1-(5-chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone(8.9 g, 37 mmol, from Oakwood) in methylene chloride (200 mL) was added1.0 M boron tribromide in methylene chloride (38.4 mL, 38.4 mmol) at−78° C. After stirring at −78° C. for 10 minutes, the reaction wasallowed to warm up to 0° C., quenched with water at 0° C., and extractedwith dichloromethane. The combined organic layers were washed withbrine, dried over sodium sulfate and filtered. After evaporating todryness under reduced pressure, the residue was used directly in nextstep (8.2 g, 98%). LCMS calculated for C₉H₉ClNO₄ (M+H)⁺: m/z=230.0.found: 230.1.

Step 2. 6-Acetyl-4-chloro-3-methyl-2-nitrophenyltrifluoromethanesulfonate

To a mixture of 1-(5-chloro-2-hydroxy-4-methyl-3-nitrophenyl)ethanone(8.6 g, 37 mmol) in methylene chloride (200 mL) was added triethylamine(16 mL, 110 mmol) followed by trifluoromethanesulfonic anhydride (9.4mL, 56 mmol) at −78° C. The reaction was allowed to warm up to roomtemperature gradually and stirred at room temperature for 30 min. Themixture was quenched with water and extracted with dichloromethane. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated to dryness. The residue was purified on silicagel, eluting with 0 to 30% ethyl acetate in hexane, to give the desiredproduct (11 g, 78% isolated yield for 2 steps). LCMS calculated forC₁₀H₈ClF₃NO₆S (M+H)⁺: m/z=362.0. found: 362.1.

Step 3. 1-(4-Chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone

A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyltrifluoromethanesulfonate (3.0 g, 8.3 mmol), (3-fluorophenyl)boronicacid (1.7 g, 12 mmol) in toluene (80 mL) and saturated sodiumbicarbonate in water (80 mL) was bubbled with N₂ to degas. Aftertetrakis(triphenylphosphine)palladium(0) (0.48 g, 0.42 mmol) was added,the mixture was bubbled with N₂ for 5 min. more and heated at 80° C. for2 hours. After cooling to r.t., the mixture was diluted with ethylacetate. The layers were separated and the aq. layer was extracted withmore ethyl acetate. The combined extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was purified onsilica gel column, eluting with 0 to 30% ethyl acetate in hexane, togive the desired product (2.35 g, 92%). LCMS calculated for C₁₅H₁₂ClFNO₃(M+H)⁺: m/z=308.0. found: 308.1.

Step 4. 1-(4-Chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanamine

A mixture of1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (50 mg, 0.2mmol) and ammonium acetate (130 mg, 1.7 mmol) in methanol (1 mL) andacetonitrile (1 mL) was heated at 65° C., in a sealed tube, for 30 min.The mixture was cooled to room temperature and sodium cyanoborohydride(22 mg, 0.35 mmol) was added. The reaction was heated at 65° C. foranother 4 hours, cooled to room temperature, quenched with saturatedsodium bicarbonate, and extracted with dichloromethane. The combinedextracts were dried over magnesium sulfate and evaporated to dryness.The residue was used directly in next step. LCMS calculated forC₁₅H₁₅ClFN₂O₂ (M+H)⁺: m/z=309.1. found: 309.1.

Step 5.N-[1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethyl]-9H-purin-6-amine

A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol),1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanamine (54 mg,0.17 mmol), and N,N-diisopropylethylamine (0.06 mL, 0.35 mmol) inisopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₀H₁₇ClFN₆O₂(M+H)⁺: m/z=427.1. found: 427.1.

Example 44-Chloro-3-(cyanomethyl)-3′-fluoro-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile

Step 1. 1-[3-Bromo-4-(bromomethyl)-5-chloro-2-methoxyphenyl]ethanone

A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (3.3g, 12 mmol), N-bromosuccinimide (2.2 g, 13 mmol), and benzoyl peroxide(0.15 g, 0.60 mmol) in carbon tetrachloride (50 mL) was heated at refluxovernight. The mixture was cooled to room temperature and concentrated.The resulting residue was diluted with ethyl acetate and washed withwater. The organic layers were dried over magnesium sulfate andevaporated to dryness. The crude product was used directly in next step.LCMS calculated for C₁₀H₁₀Br₂ClO₂ (M+H)⁺: m/z=355.1. found: 355.1.

Step 2.6-Acetyl-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile

To a mixture of sodium cyanide (100 mg, 2.0 mmol) in water (0.5 mL) wasadded sulfuric acid (0.95 g, 0.97 mmol) at 0° C. (the reaction generateshydrogen cyanide and must be run in a fume hood with good ventilation),followed by a solution of6-acetyl-3-(bromomethyl)-4-chloro-3′-fluorobiphenyl-2-carbonitrile (70mg, 0.2 mmol) in acetonitrile (2 mL). The reaction was heated at 80° C.for 1 hour with pH adjustment to 9 by addition of solid sodium cyanide.The reaction mixture was cooled and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over sodiumsulfate and concentrated to dryness under reduced pressure. The residuewas purified on silica gel, eluting with 0 to 40% ethyl acetate inhexane. LCMS calculated for C₁₇H₁₁ClFN₂O (M+H)⁺: m/z=313.1. found:313.1.

Step 3.6-(1-Aminoethyl)-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile

A mixture of6-acetyl-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile(0.020 g, 0.064 mmol) and ammonium acetate (49 mg, 0.64 mmol) inmethanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in asealed tube for 30 min. The mixture was cooled to room temperature andsodium cyanoborohydride (8 mg, 0.13 mmol) was added. The reaction washeated at 65° C. for another 4 hours, cooled to room temperature,quenched with saturated sodium bicarbonate and extracted withdichloromethane. The combined extracts were dried over magnesium sulfateand evaporated to dryness. The residue was used directly in next step(20 mg, 100%). LCMS calculated for C₁₇H₁₄ClFN₃ (M+H)⁺: m/z=314.1. found:313.9.

Step 4.4-Chloro-3-(cyanomethyl)-3′-fluoro-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile

A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol),6-(1-aminoethyl)-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile(17 mg, 0.054 mmol), and N,N-diisopropylethylamine (0.032 mL, 0.18 mmol)in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product (8 mg, 30%). LCMS calculated forC₂₂H₁₆ClFN₇ (M+H)⁺: m/z=432.1. found: 432.1.

Example 51-{4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-one

Step 1. 1-(6-Amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone

A mixture of1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone (4.4 g, 14mmol) in methanol (80 mL) was hydrogenated in the presence of 5% Pt/C(443 mg) under balloon pressure of hydrogen overnight. The catalyst wasfiltered and the filtrate was concentrated under reduced pressure togive the desired product (4.0 g, 100%). LCMS calculated for C₁₅H₁₄ClFNO(M+H)⁺: m/z=278.1. found: 278.1.

Step 2.1-(6-Acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one

To a mixture of1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg,0.4 mmol) and 4-dimethylaminopyridine (52.8 mg, 0.432 mmol) intetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.044 mL,0.40 mmol). The reaction was stirred at room temperature for 1 hour.Potassium tert-butoxide (1.0 M) in tetrahydrofuran (0.79 mL, 0.79 mmol)was added and the resulting mixture was stirred at room temperature for2 hours, then quenched with aq. ammonium chloride and extracted withethyl acetate. The combined organic layers were washed with water,brine, dried and evaporated. The resulting residue was purified onsilica gel, eluting with 0 to 50% ethyl acetate in hexane, to give theproduct (40 mg, 30%). LCMS calculated for C₁₉H₁₈ClFNO₂ (M+H)⁺:m/z=346.1. found: 346.1.

Step 3.1-[6-(1-Aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]pyrrolidin-2-one

A mixture of1-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one(40 mg, 0.1 mmol) and ammonium acetate (89 mg, 1.2 mmol) and sodiumcyanoborohydride (15 mg, 0.23 mmol) in methanol (0.4 mL) andacetonitrile (0.4 mL) was heated at 65° C. overnight in a sealed tube.The mixture was cooled to room temperature and quenched with saturatedsodium bicarbonate and extracted with dichloromethane. The combinedextracts were dried over magnesium sulfate and evaporated to dryness.The crude product was used directly in next step (34 mg, 80%). LCMScalculated for C₁₉H₁₈ClFNO (M−NH₂)⁺: m/z=330.1. found: 330.0.

Step 4.1-{4-Chloro-3′-fluoro-3-methyl-6-[7-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-one

A mixture of 6-bromo-9H-purine (21 mg, 0.11 mmol),1-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]pyrrolidin-2-one(34 mg, 0.098 mmol), and N,N-diisopropylethylamine (0.034 mL, 0.20 mmol)in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₄H₂₃ClFN₆O(M+H)⁺: m/z=465.2. found: 465.1.

Example 61-{4-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-onetrifluoroacetate

Step 1.1-(4-Chloro-3′,5′-difluoro-5-methyl-6-nitrobiphenyl-2-yl)ethanone

A biphasic solution of 6-acetyl-4-chloro-3-methyl-2-nitrophenyltrifluoromethanesulfonate (9.6 g, 26 mmol) and(3,5-difluorophenyl)boronic acid (5.0 g, 32 mmol) in toluene (100 mL)and saturated sodium bicarbonate in water (100 mL) was bubbled with N₂to degas. After tetrakis(triphenylphosphine)palladium(0) (1.22 g, 1.06mmol) was added, the mixture was bubbled with N₂ for 5 min. more andheated at 80° C. for 2 hours. The mixture was cooled to room temperatureand diluted with ethyl acetate. The layers were separated and the aq.layer was extracted with more ethyl acetate. The combined extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel column, eluting with 0-30% ethylacetate in hexane, to give the desired product. LCMS calculated forC₁₅H₁₁ClF₂NO₃ (M+H)⁺: m/z=326.0. found: 326.0.

Step 2.1-(6-Amino-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone

Into a flask was placed a suspension of iron (1.50 g, 26.9 mmol) (<10μm) in ethanol (22 mL) δ 0 M hydrogen chloride in water (0.374 mL, 2.24mmol) was added and the suspension was stirred for 2 h at 60° C. Asolution of 5.0 M ammonium chloride in water (3.86 mL, 19.3 mmol) wasadded followed by a solution of1-[4-chloro-3′,5′-difluoro-6-(hydroxyamino)-5-methylbiphenyl-2-yl]ethanone(1.4 g, 4.5 mmol) in ethanol (5.2 mL). The resulting suspension wasstirred at 60° C. for 1 hour. The mixture was cooled, filtered andevaporated in vacuo. The residue was dissolved in a mixture of ethylacetate and saturated sodium bicarbonate solution and stirred for a fewminutes. The layers were separated and the ethyl acetate layer waswashed with brine, dried over MgSO₄ and evaporated in vacuo to give thedesired product (0.95 g, 72%). LCMS calculated for C₁₅H₁₃ClF₂NO (M+H)⁺:m/z=296.1. found: 296.0.

Step 3.1-(6-Acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one

To a mixture of1-(6-amino-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.10g, 0.34 mmol) and pyridine (0.041 mL, 0.51 mmol) in methylene chloride(2 mL) was added 4-chlorobutanoyl chloride (0.042 mL, 0.37 mmol). Thereaction was stirred at room temperature for 1 hour, quenched withsaturated sodium bicarbonate solution and extracted with ethyl acetate.The combined extracts were dried over MgSO₄ and concentrated to drynessunder reduced pressure. The resulting residue was treated with 1.0 Mpotassium tert-butoxide in tetrahydrofuran (0.84 mL, 0.84 mmol) intetrahydrofuran (2 mL) at room temperature for 2 hours. The reaction wasquenched with aq. NH₄Cl, extracted with ethyl acetate. The combinedorganic layers were washed with water and brine, dried over MgSO₄ andevaporated. The residue was purified on silica gel (eluting with 0-40%of ethyl acetate in hexanes) to give the desired product (15 mg, 12%),LCMS calculated for C₁₉H₁₇ClF₂NO₂ (M+H)⁺: m/z=364.1. found: 364.1.

Step 4.1-[6-(1-Aminoethyl)-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-yl]pyrrolidin-2-one

A mixture of1-(6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-yl)pyrrolidin-2-one(0.015 g, 0.041 mmol), ammonium acetate (0.032 g, 0.41 mmol), 1.0 Msodium cyanoborohydride in tetrahydrofuran (0.10 mL, 0.10 mmol) inmethanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65° C.overnight. The mixture was cooled to room temperature, quenched withsaturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were dried over MgSO₄ andconcentrated to give the desired product. LCMS calculated forC₁₉H₁₇ClF₂NO (M−NH₂)⁺: m/z=348.1. found: 348.0.

Step 5.1-{4-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-onetrifluoroacetate

A mixture of1-[6-(1-aminoethyl)-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-yl]pyrrolidin-2-one(0.014 g, 0.038 mmol), 6-bromo-9H-purine (0.011 g, 0.058 mmol) andN,N-diisopropylethylamine (0.013 mL, 0.077 mmol) in ethanol (0.2 mL) washeated at 100° C. overnight. The mixture was purified on prep LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.05% trifluoroacetic acid, at flow rate of 30 mL/min, to affordthe desired product as TFA salt. LCMS calculated for C₂₄H₂₂ClF₂N₆O(M+H)⁺: m/z=483.1. found: 483.1.

Example 73-{4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-1,3-oxazolidin-2-one

Step 1.3-(6-Acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)-1,3-oxazolidin-2-one

To a mixture of1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg,0.4 mmol) and 4-dimethylaminopyridine (53 mg, 0.43 mmol) intetrahydrofuran (1 mL) was added 2-chloroethyl chloridocarbonate (0.041mL, 0.40 mmol). The mixture was stirred at room temperature overnight.To the mixture was added 1.0 M potassium tert-butoxide intetrahydrofuran (0.79 mL) at 0° C., and the resulting mixture stirred atroom temperature for 2 hours, then quenched with aq. ammonium chloride,extracted with ethyl acetate. The combined organic layers were washedwith brine, dried, and evaporated. The filtrate was applied on silicagel, eluting with 0 to 60% ethyl acetate in hexane, to give the desiredproduct (14 mg, 10%). LCMS calculated for C₁₈H₁₆ClFNO₃ (M+H)⁺:m/z=348.1. found: 348.0.

Step 2.3-[6-(1-Aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]-1,3-oxazolidin-2-one

A mixture of3-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)-1,3-oxazolidin-2-one(14 mg, 0.040 mmol) and ammonium acetate (31 mg, 0.40 mmol) and sodiumcyanoborohydride (5 mg, 0.08 mmol) in methanol (0.1 mL) and acetonitrile(0.1 mL) was heated at 65° C. overnight in a sealed tube. The mixturewas cooled to room temperature, quenched with saturated sodiumbicarbonate and extracted with dichloromethane. The combined extractswere dried over magnesium sulfate and evaporated to dryness. The crudeproduct was used directly in next step (10 mg, 70%). LCMS calculated forC₁₈H₁₆ClFNO₂ (M−NH₂)⁺: m/z=332.1. found: 332.1.

Step 3.3-{4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-1,3-oxazolidin-2-one

A mixture of 6-bromo-9H-purine (6.3 mg, 0.032 mmol),3-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]-1,3-oxazolidin-2-one(10 mg, 0.03 mmol), and N,N-diisopropylethylamine (0.010 mL, 0.057 mmol)in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min, to give the desired. LCMS calculated for C₂₃H₂₁ClFN₆O₂ (M+H)⁺:m/z=467.1. found: 467.1.

Example 8N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

Step 1.1-[4-Chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanone

A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile(100 mg, 0.3 mmol), azidotrimethylsilane (0.092 mL, 0.69 mmol), anddibutyloxostannane (13 mg, 0.052 mmol) in toluene (2.9 mL) was heated atreflux overnight. The mixture was evaporated to dryness and purified onsilica gel, eluting with 0 to 50% ethyl acetate in hexane, to give thedesired product (85 mg, 70%). LCMS calculated for C₁₆H₁₃ClFN₄O (M+H)⁺:m/z=331.1. found: 331.0.

Step 2.1-[4-Chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanamine

A mixture of1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanone(85 mg, 0.26 mmol), ammonium acetate (198 mg, 2.57 mmol) and sodiumcyanoborohydride (32 mg, 0.51 mmol) in methanol (0.9 mL) andacetonitrile (0.9 mL) was heated at 65° C. overnight in a sealed tube.The mixture was cooled to room temperature and quenched with saturatedsodium bicarbonate and extracted with ethyl acetate. The combinedextracts were dried over magnesium sulfate and evaporated to dryness.The crude product was used directly in next step (45 mg, 53%). LCMScalculated for C₆H₁₃ClFN₄ (M−NH₂)⁺: m/z=315.1. found: 315.1.

Step 3.N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

A mixture of 6-bromo-9H-purine (30 mg, 0.15 mmol),1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethanamine(45 mg, 0.14 mmol), and N,N-diisopropylethylamine (0.047 mL, 0.27 mmol)in isopropyl alcohol (0.5 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₁H₁₈ClFN₉(M+H)⁺: m/z=450.1. found: 450.1.

Example 9N-[4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl]acetamide

Step 1.N-acetyl-N-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)acetamide

To a mixture of1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg,0.4 mmol) in methylene chloride (2 mL) was addedN,N-diisopropylethylamine (0.094 mL, 0.54 mmol) followed by acetylchloride (0.038 mL, 0.53 mmol). The mixture was stirred at roomtemperature for 30 minutes, quenched with water and extracted with ethylacetate. The combined organic layers were washed with brine and driedover sodium sulfate and concentrated. The residue was purified on silicagel, eluting with 0 to 60% ethyl acetate in hexane, to give the desiredproducts (57 mg, 40%). LCMS calculated for C₁₉H₁₈ClFNO₃ (M+H)⁺:m/z=362.1. found: 362.0.

Step 2.N-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]acetamide

A mixture ofN-acetyl-N-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)acetamide(57 mg, 0.16 mmol), ammonium acetate (120 mg, 1.6 mmol) and sodiumcyanoborohydride (20 mg, 0.32 mmol) in methanol (0.6 mL) andacetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube.The mixture was then cooled to room temperature and quenched withsaturated sodium bicarbonate and extracted with ethyl acetate. Thecombined extracts were dried over magnesium sulfate and evaporated todryness. The crude product was used directly in next step. LCMScalculated for C₁₇H₁₉ClFN₂O (M+H)⁺: m/z=321.1. found: 321.0.

Step 3.N-{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}acetamide

A mixture of 6-bromo-9H-purine (22 mg, 0.11 mmol),N-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]acetamide(32 mg, 0.10 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.20 mmol)in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₂H₂₁ClFN₆O(M+H)⁺: m/z=439.1. found: 439.3.

Example 10 Dimethyl{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}imidodicarbonate

Step 1. Dimethyl(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)imidodicarbonate

To a mixture of1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg,0.4 mmol) in methylene chloride (2 mL) was addedN,N-diisopropylethylamine (0.094 mL, 0.54 mmol) followed by methylchloroformate (0.033 mL, 0.43 mmol). The mixture was stirred at roomtemperature for 30 min. To the reaction mixture was added a catalyticamount of DMAP and another equivalent of methyl chloroformate. Thereaction was stirred at room temperature over a weekend, quenched withwater and extracted with ethyl acetate. The combined organic layers werewashed with brine and dried over sodium sulfate, then concentrated. Theresidue was purified on silica gel, eluting with 0 to 50% ethyl acetatein hexane, to give the bis-acylated product (67 mg, 50%). LCMScalculated for C₁₉H₁₈ClFNO₅ (M+H)⁺: m/z=394.1. found: 394.1.

Step 2. Dimethyl[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]imidodicarbonate

A mixture of dimethyl(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)imidodicarbonate (67mg, 0.17 mmol), ammonium acetate (131 mg, 1.70 mmol) and sodiumcyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) andacetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube.The mixture was then cooled to room temperature and quenched withsaturated sodium bicarbonate and extracted with dichloromethane. Thecombined extracts were dried over magnesium sulfate and evaporated todryness. The crude product was used directly in next step (67 mg, 100%).LCMS calculated for C₁₉H₂₁ClFN₂O₄ (M+H)⁺: m/z=395.1. found: 395.1.

Step 3. Dimethyl{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}imidodicarbonate

A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol), dimethyl[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]imidodicarbonate(66 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol)in isopropyl alcohol (0.6 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired. LCMS calculated for C₂₄H₂₃ClFN₆O₄ (M+H)⁺:m/z=513.1. found: 513.2.

Example 11N-{1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

Step 1.1-[4-Chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanone

1,2-Hydrazinedicarboxaldehyde (0.095 g, 1.1 mmol) and then, drop bydrop, chlorotrimethylsilane (0.69 mL, 5.4 mmol) and triethylamine (0.35mL, 2.5 mmol) were added to a suspension of1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g,0.36 mmol) in pyridine (2 mL). The mixture was heated at 100° C.overnight. Evaporation at reduced pressure of the solvent yielded asolid that was treated with water and extracted with dichloromethane.The extracts were dried over sodium sulfate and concentrated. The residewas purified on silica gel, eluting with 0 to 50% ethyl acetate inhexane, then 0 to 10% methanol in dichloromethane, to give the desiredproduct (44 mg, 37%). LCMS calculated for C₁₇H₁₄ClFN₃O (M+H)⁺:m/z=330.1. found: 330.0.

Step 2.1-[4-Chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanamine

A mixture of1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanone(44 mg, 0.13 mmol), ammonium acetate (103 mg, 1.33 mmol) and sodiumcyanoborohydride (17 mg, 0.27 mmol) in methanol (0.5 mL) andacetonitrile (0.5 mL) was heated at 65° C. overnight in a sealed tube.The mixture was then cooled to room temperature and quenched withsaturated sodium bicarbonate and extracted with dichloromethane. Thecombined extracts were dried over magnesium sulfate and evaporated todryness. The crude product was used directly in next step (15 mg, 34%).LCMS calculated for C₁₇H₁₇ClFN₄ (M+H)⁺: m/z=331.1. found: 331.1.

Step 3.N-{1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

A mixture of 6-bromo-9H-purine (10 mg, 0.050 mmol),1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethanamine(15 mg, 0.045 mmol), and N,N-diisopropylethylamine (0.016 mL, 0.091mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₂H₁₉ClFN₈(M+H)⁺: m/z=449.1. found: 449.1.

Example 12N-{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-N-(methylsulfonyl)methanesulfonamide

Step 1.N-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-A-N-(methylsulfonyl)methanesulfonamide

To a mixture of1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (50 mg, 0.2mmol) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (33mg, 0.27 mmol) followed by methanesulfonyl chloride (0.017 mL, 0.22mmol). The mixture was stirred for 2 hours, quenched with water andextracted with ethyl acetate. The combined organic layers were washedwith brine and dried over sodium sulfate and concentrated. The residuewas purified on silica gel, eluting with 0 to 40% ethyl acetate inhexane, to give the desired product (25 mg, 30%). LCMS calculated forC₁₇H₁₈ClFNO₅S₂ (M+H)⁺: m/z=434.0. found: 434.1.

Step 2.N-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]-Nethylsulfonyl)methanesulfonamide

A mixture ofN-(6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl)-N-(methylsulfonyl)methanesulfonamide(25 mg, 0.058 mmol), ammonium acetate (44 mg, 0.58 mmol) and sodiumcyanoborohydride (7 mg, 0.12 mmol) in methanol (0.2 mL) and acetonitrile(0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixturewas then cooled to room temperature and quenched with saturated sodiumbicarbonate and extracted with dichloromethane. The combined extractswere dried over magnesium sulfate and evaporated to dryness. The crudeproduct was used directly in next step (21 mg, 84%). LCMS calculated forC₁₇H₁₈ClFNO₄S₂ (M−NH₂)⁺: m/z=418.0. found: 418.0.

Step 3.N-{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-N-(methylsulfonyl)methanesulfonamide

A mixture of 6-bromo-9H-purine (10 mg, 0.053 mmol),N-[6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]-Nethylsulfonyl)methanesulfonamide(21 mg, 0.048 mmol), and N,N-diisopropylethylamine (0.017 mL, 0.096mmol) in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₂H₂₃ClFN₆O₄S₂(M+H)⁺: m/z=553.1. found: 553.1.

Example 13N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine

Step 1. 1-(3-Bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone

To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone(10 g, 54 mmol, from Aldrich) in acetic acid (100 mL) was addedN-bromosuccinimide (12 g, 65 mmol) and the resulting mixture was stirredat room temperature for 18 hours. The reaction mixture was concentratedin vacuo, neutralized with saturated sodium bicarbonate and filtered toremove insoluble succinimide. The filtrate was extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, and then concentrated to dryness under reduced pressure.The crude product was recrystallized from a mixture of ethyl acetate andhexane (11.4 g, 80%).

Step 2. 6-Acetyl-2-bromo-4-chloro-3-methylphenyltrifluoromethanesulfonate

To a mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone(11 g, 40 mmol) in methylene chloride (200 mL) was added triethylamine(17 mL, 120 mmol) followed by trifluoromethanesulfonic anhydride (10 mL,60 mmol) at −78° C. The reaction was allowed to warm up to roomtemperature gradually and stirred at room temperature for 30 min. Afterthe mixture was evaporated under reduced pressure at room temperature,the residue was diluted with ethyl acetate and washed with water. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated to dryness. The residue was purified on silicagel, eluting with 0 to 30% ethyl acetate in hexane, to give the desiredproduct (13.6 g, 86%). LCMS calculated for C₁₀H₈BrClF₃O₄S (M+H)⁺:m/z=394.9. found: 394.9.

Step 3. 1-(6-Bromo-4-chloro-5-methylbiphenyl-2-yl)ethanone

A biphasic solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyltrifluoromethanesulfonate (3.3 g, 8.3 mmol) and phenylboronic acid (1.2g, 10 mmol) in toluene (30 mL) and saturated sodium bicarbonate in water(30 mL) was bubbled with N₂ to degas. Aftertetrakis(triphenylphosphine)palladium(0) (0.385 g, 0.333 mmol) wasadded, the mixture was bubbled with N₂ for 5 min. more and heated at 80°C. for 2 hours. After cooling to r.t., the mixture was diluted withethyl acetate. The layers were separated and the aq. layer was extractedwith more ethyl acetate. The combined extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The residue was purifiedon silica gel column, eluting with 0-20% of ethyl acetate in hexane, togive the desired product (2.5 g, 93%). LCMS calculated for C₁₅H₁₃BrClO(M+H)⁺: m/z=323.0. found: 323.0.

Step 4.1-[4-Chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanone

A biphasic solution of1-(6-bromo-4-chloro-5-methylbiphenyl-2-yl)ethanone (0.20 g, 0.62 mmol)and (2,6-difluoropyridin-4-yl)boronic acid (0.12 g, 0.74 mmol) in1,4-dioxane (2.0 mL) and 10% Na₂CO₃ in water (0.98 mL, 0.93 mmol)) wasbubbled with N₂ to degas. After tetrakis(triphenylphosphine)palladium(0)(29 mg, 0.025 mmol) was added the mixture was bubbled with N₂ for 5 min.and heated at 100° C. overnight. The mixture was cooled to roomtemperature and diluted with ethyl acetate. The layers were separatedand the aq. layer was extracted with more ethyl acetate. The combinedextracts were washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel column, elutingwith 0-30% of ethyl acetate in hexane, to give the desired product (60mg, 30%). LCMS calculated for C₂₀H₁₅ClF₂NO (M+H)⁺: m/z=358.1. found:358.0.

Step 5.1-[4-Chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanamine

A mixture of1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanone(60 mg, 0.2 mmol), ammonium acetate (130 mg, 1.7 mmol) and sodiumcyanoborohydride (21 mg, 0.34 mmol) in methanol (0.6 mL) andacetonitrile (0.6 mL) was heated at 65° C. overnight in a sealed tube.The mixture was then cooled to room temperature and quenched withsaturated sodium bicarbonate and extracted with dichloromethane. Thecombined extracts were dried over magnesium sulfate and evaporated todryness. The crude product was used directly in next step (60 mg, 100%).LCMS calculated for C₂₀H₁₅ClF₂N (M−NH₂)⁺: m/z=342.1. found: 342.1.

Step 5.N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine

A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol),1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethanamine(60 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol)in isopropyl alcohol (0.6 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₅H₂₀ClF₂N₆(M+H)⁺: m/z=477.1. found: 477.1.

Example 181-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one

Step 1. 1-(3-Amino-5-chloro-2-methoxy-4-methylphenyl)ethanone

1-(5-Chloro-2-methoxy-4-methyl-3-nitrophenyl)ethanone (5.0 g, 20 mmol)was hydrogenated in 100 mL of methanol in the presence of 0.5 g of 10%Pt/C, under a balloon pressure of hydrogen overnight. The catalyst wasfiltered off and the filtrate was concentrated. The residue wasdissolved in dichloromethane and dried over sodium sulfate and thenevaporated to dryness. The crude product was used directly in next step(4.4 g, 100%). LCMS calculated for C₁₀H₁₃ClNO₂ (M+H)⁺: m/z=214.1. found:214.1.

Step 2. 1-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)pyrrolidin-2-one

To a mixture of 1-(3-amino-5-chloro-2-methoxy-4-methylphenyl)ethanone(100 mg, 0.5 mmol) and 4-dimethylaminopyridine (69 mg, 0.56 mmol) intetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.058 mL,0.52 mmol). The reaction was stirred at room temperature for 1 hour. Tothe reaction mixture was added 1.0 M potassium tert-butoxide intetrahydrofuran (1.03 mL, 1.03 mmol). The resulting mixture was stirredat room temperature for 2 hours, quenched with aq. ammonium chloride andextracted with ethyl acetate. The combined organic layers were washedwith water, brine, dried and evaporated. The residue was purified onsilica gel, eluting with 0 to 50% ethyl acetate in hexane, to give theproduct (20 mg, 20%). LCMS calculated for C₁₄H₁₇ClNO₃ (M+H)⁺: m/z=282.1.found: 282.1.

Step 3.1-[3-(1-Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrolidin-2-one

A mixture of1-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)pyrrolidin-2-one (20 mg,0.07 mmol), ammonium acetate (55 mg, 0.71 mmol) and sodiumcyanoborohydride (9.0 mg, 0.14 mmol) in methanol (0.2 mL) andacetonitrile (0.2 mL) was heated at 65° C. overnight in a sealed tube.The mixture was cooled to room temperature, quenched with saturatedsodium bicarbonate and extracted with dichloromethane. The combinedextracts were dried over magnesium sulfate and evaporated to dryness.The crude product was used directly in next step (11 mg, 50%). LCMScalculated for C₁₄H₂₀ClN₂O₂ (M+H)⁺: m/z=283.1. found: 283.1.

Step 4.1-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one

A mixture of 6-bromo-9H-purine (8.5 mg, 0.043 mmol),1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrolidin-2-one(11 mg, 0.039 mmol), and N,N-diisopropylethylamine (0.014 mL, 0.078mmol) in isopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₁₉H₂₂ClN₆O₂(M+H)⁺: m/z=401.1. found: 401.1.

Example 194-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide

Step 1. 6-Acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile

A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyltrifluoromethanesulfonate (4.5 g, 13 mmol) and(3,5-difluorophenyl)boronic acid (2.5 g, 16 mmol) in toluene (50 mL) andsaturated sodium bicarbonate in water (50 mL) was bubbled with N₂ todegas. After tetrakis(triphenylphosphine)palladium(0) (0.61 g, 0.53mmol) was added, the mixture was bubbled with N₂ for 5 min. and thenheated at 80° C. for 2 hours. The mixture was cooled to room temperatureand diluted with ethyl acetate. The layers were separated and the aq.layer was extracted with more ethyl acetate. The combined extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified on silica gel column, eluting with 0-30% of ethylacetate in hexane, to give the desired product (1.94 g, 48%). LCMScalculated for C₁₆H₁₁ClF₂NO (M+H)⁺: m/z=306.0. found: 306.0.

Step 2. 6-Acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide

A mixture of6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carbonitrile (0.20g, 0.65 mmol) and potassium hydroxide (0.074 g, 1.3 mmol) in ethanol(0.9 mL) was refluxed for 2 hours. After cooled, the mixture wasacidified with 1 N HCl and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate, andevaporated to dryness under reduced pressure. The crude mixture waspurified on silica gel, eluting with 0 to 80% ethyl acetate in hexane,to yield the desired product (61 mg, 29%). LCMS calculated forC₁₆H₁₃ClF₂NO₂ (M+H)⁺: m/z=324.1. found: 324.0.

Step 3.6-(1-Aminoethyl)-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide

A mixture of6-acetyl-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide (61 mg,0.19 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodiumcyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) andacetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube.The mixture was then cooled to room temperature, quenched with saturatedsodium bicarbonate and extracted with ethyl acetate. The combinedextracts were dried over magnesium sulfate and evaporated to dryness.The crude product was used directly in next step (61 mg, 99%). LCMScalculated for C₁₆H₁₃ClF₂NO (M−NH₂)⁺: m/z=308.1. found: 308.0.

Step 4.4-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide

A mixture of 6-bromo-9H-purine (41 mg, 0.21 mmol),6-(1-aminoethyl)-4-chloro-3′,5′-difluoro-3-methylbiphenyl-2-carboxamide(61 mg, 0.19 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.38 mmol)in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₁H₁₈ClF₂N₆O(M+H)⁺: m/z=443.1. found: 443.1.

Example 20N-(1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethyl)-9H-purin-6-amine

Step 1. 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone

A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (10g, 38 mmol), dimethyl sulfate (4.3 mL, 46 mmol) and potassium carbonate(11 g, 76 mmol) in acetone (200 mL) was heated at reflux overnight.After evaporation to dryness, the mixture was diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate, and evaporated to dryness. Theresidue was purified on silica gel, eluting with 0 to 20% ethyl acetatein hexane, to yield the desired product (8.8 g, 84%). LCMS calculatedfor C₁₀H₁₁BrClO₂ (M+H)⁺: m/z=277.0. found: 277.0.

Step 2.1-{5-Chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethanone

A biphasic solution of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.10 g, 0.36mmol) andN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(0.11 g, 0.43 mmol) in 1,4-dioxane (1.2 mL) and 10% sodium carbonate inwater (0.57 mL, 0.54 mmol) was bubbled with N₂ to degas. Aftertetrakis(triphenylphosphine)palladium(0) (17 mg, 0.014 mmol) was added,the mixture was bubbled with N₂ for 5 min. and heated at 100° C.overnight. The mixture was cooled to r.t. and diluted with ethylacetate. The layers were separated and the aq. layer was extracted withmore ethyl acetate. The combined extracts were washed with brine, driedover Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel column, eluting with 0-30% of ethyl acetate in hexane, togive the desired product (60 mg, 50%). LCMS calculated for C₁₆H₁₉ClN₃O₂(M+H)⁺: m/z=320.1. found: 320.1.

Step 3.5-[3-(1-Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyrimidin-2-amine

A mixture of1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethanone(60 mg, 0.2 mmol), ammonium acetate (150 mg, 1.9 mmol) and sodiumcyanoborohydride (24 mg, 0.38 mmol) in methanol (0.7 mL) andacetonitrile (0.7 mL) was heated at 65° C. overnight in a sealed tube.The mixture was cooled to room temperature, quenched with saturatedsodium bicarbonate and extracted with ethyl acetate. The combinedextracts were dried over magnesium sulfate and evaporated to dryness.The crude product was used directly in next step (60 mg, 100%). LCMScalculated for C₁₆H₂₂ClN₄O (M+H)⁺: m/z=321.1. found: 321.1.

Step 4.N-(1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethyl)-9H-purin-6-amine

A mixture of 6-bromo-9H-purine (41 mg, 0.20 mmol),5-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyrimidin-2-amine(60 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.37 mmol)in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₁H₂₄ClN₈O(M+H)⁺: m/z=439.2. found: 439.1. ¹H NMR (DMSO-d₆, 400 MHz) δ 12.91 (1H,br s), 8.29 (2H, s), 8.20 (1H, m), 8.13 (1H, s), 8.10 (1H, s), 7.61 (1H,s), 5.73 (1H, m), 3.46 (3H, s), 3.16 (6H, s), 2.06 (3H, s), 1.47 (3H, d,J=6.8 Hz) ppm.

Example 601-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}piperidin-4-61

Step 1. 1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone

To a stirred solution of 1-(5-chloro-2-hydroxy-4-methylphenyl)ethanone(20 g, 110 mmol) in acetic acid (200 mL) was added N-iodosuccinimide (29g, 130 mmol) and the resulting mixture was stirred at room temperaturefor 18 hours. The reaction mixture was concentrated in vacuo,neutralized with saturated sodium bicarbonate, filtered off insolublesuccinimide and extracted with ethyl acetate. The combined organiclayers were washed with brine, dried over sodium sulfate, filtered andconcentrated to dryness under reduced pressure. The crude product wasrecrystallized from a mixture of ethyl acetate and hexane (25.8 mg,77%). LCMS calculated for C₉H₉ClIO₂ (M+H)⁺: m/z=311.0. found: 311.0.

Step 2. 1-(5-Chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone

A mixture of 1-(5-chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (10 g,32 mmol), dimethyl sulfate (3.7 mL, 39 mmol) and potassium carbonate(8.9 g, 64 mmol) in acetone (200 mL) was heated at reflux overnight.After evaporation to dryness, the mixture was diluted with water andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered and evaporated todryness. The residue was purified on silica gel, eluting with 0 to 20%ethyl acetate in hexane, to yield the desired product (8.99 g, 86%).LCMS calculated for C₁₀H₁₁ClIO₂ (M+H)⁺: m/z=324.9. found: 324.9.

Step 3.1-[5-Chloro-3-(4-hydroxypiperidin-1-yl)-2-methoxy-4-methylphenyl]ethanone

To a mixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone(150 mg, 0.46 mmol) and 4-hydroxypiperidine (56 mg, 0.56 mmol) inisopropyl alcohol (1 mL) was added 1,2-ethanediol (0.052 mL, 0.92 mmol),potassium phosphate (200 mg, 0.93 mmol), and copper(I) iodide (5 mg,0.02 mmol). The reaction was heated at 80° C. overnight and then cooledto room temperature. Water was added, and the mixture was extracted withethyl acetate. The combined organic phases were washed with brine anddried over sodium sulfate, filtered and concentrated to dryness. Theresidue was purified on silica gel, eluting with 0 to 50% ethyl acetatein hexanes, to give the desired product (15 mg, 11%). LCMS calculatedfor C₁₅H₂₁ClNO₃ (M+H)⁺: m/z=298.1. found: 298.0.

Step 4.1-[3-(1-Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]piperidin-4-ol

A mixture of1-[5-chloro-3-(4-hydroxypiperidin-1-yl)-2-methoxy-4-methylphenyl]ethanone(15 mg, 0.050 mmol), ammonium acetate (39 mg, 0.50 mmol) and sodiumcyanoborohydride (6 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile(0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixturewas then cooled to room temperature, quenched with saturated sodiumbicarbonate and extracted with dichloromethane. The combined extractswere dried over magnesium sulfate, filtered and concentrated to dryness.The resulting crude product was used directly in next step (7 mg, 50%).LCMS calculated for C₁₅H₂₄ClN₂O₂ (M+H)⁺: m/z=299.1. found: 299.1.

Step 5.1-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}piperidin-4-ol

A mixture of 6-bromo-9H-purine (5 mg, 0.03 mmol),1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]piperidin-4-ol (7mg, 0.02 mmol), and N,N-diisopropylethylamine (0.0082 mL, 0.047 mmol) inisopropyl alcohol (0.1 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₀H₂₆ClN₆O₂(M+H)⁺: m/z=417.2. found: 417.1.

Example 613′-Chloro-4-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide

Step 1. Methyl3′-acetyl-5′-chloro-4-fluoro-2″-methoxy-6′-methylbiphenyl-3-carboxylate

A biphasic solution of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.800 g, 2.88mmol) and [4-fluoro-3-(methoxycarbonyl)phenyl]boronic acid (0.684 g,3.45 mmol) in 1,4-dioxane (9.3 mL) and 10% sodium carbonate in water(4.58 mL, 4.32 mmol) was bubbled with N₂ to degas. Aftertetrakis(triphenylphosphine)palladium(0) (133 mg, 0.115 mmol) was added,the mixture was bubbled with N₂ for 5 min and heated at 100° C.overnight. The mixture was cooled to room temperature and diluted withethyl acetate. The layers were separated and the aq. layer was extractedwith more ethyl acetate. The combined extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated to crude product. LCMScalculated for C₁₈H₁₇ClFO₄ (M+H)⁺: m/z=351.1. found: 351.1.

Step 2,3′-Acetyl-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxamide

A mixture of methyl3′-acetyl-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxylate(50 mg, 0.1 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) washeated at 90° C. in a sealed tube overnight. After evaporating themixture to dryness, the residue was used directly in next step. LCMScalculated for C₁₇H₁₆ClFNO₃ (M+H)⁺: m/z=336.1. found: 336.0.

Step 3.3′-(1-Aminoethyl)-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxamide

A mixture of3′-acetyl-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxamide(50 mg, 0.1 mmol), ammonium acetate (115 mg, 1.49 mmol) and sodiumcyanoborohydride (19 mg, 0.30 mmol) in methanol (0.5 mL) andacetonitrile (0.5 mL) was heated at 65° C. overnight in a sealed tube.The mixture was then cooled to room temperature, quenched with saturatedsodium bicarbonate and extracted with dichloromethane. The combinedextracts were dried over magnesium sulfate, filtered and concentrated todryness. The resulting crude product was used directly in next step (36mg, 70%). LCMS calculated for C₁₇H₁₆ClFNO₂ (M−NH₂)⁺: m/z=320.1. found:320.1.

Step 4.3′-Chloro-4-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide

A mixture of 6-bromo-9H-purine (23 mg, 0.12 mmol),3′-(1-aminoethyl)-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxamide(36 mg, 0.11 mmol), and N,N-diisopropylethylamine (0.037 mL, 0.21 mmol)in isopropyl alcohol (0.4 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₂H₂₁ClFN₆O₂(M+H)⁺: m/z=455.1. found: 455.1.

Example 623′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide

Step 1. Methyl3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylat

A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0g, 3.6 mmol) and [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (0.85g, 4.3 mmol) in 1,4-dioxane (12 mL) and 10% sodium carbonate in water(5.73 mL, 5.40 mmol) was bubbled with N₂ to degas. Aftertetrakis(triphenylphosphine)palladium(0) (166 mg, 0.144 mmol) was added,the mixture was bubbled with N₂ for 5 min. more and heated at 100° C.overnight. The mixture was cooled to room temperature and diluted withethyl acetate. The layers were separated and the aq. layer was extractedwith more ethyl acetate. The combined extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated to give crude product.

Step 2.3′-Acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide

A mixture of methyl3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate(25 mg, 0.071 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) washeated at 90° C. in a sealed tube overnight. After evaporating themixture to dryness, the residue was used directly in next step.

Step 3.3′-(1-Aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide

A mixture of3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide(25 mg, 0.074 mmol), ammonium acetate (57 mg, 0.74 mmol) and sodiumcyanoborohydride (9 mg, 0.15 mmol) in methanol (0.3 mL) and acetonitrile(0.3 mL) was heated at 65° C. overnight in a sealed tube. The mixturewas cooled to room temperature, quenched with saturated sodiumbicarbonate and extracted with dichloromethane. The combined extractswere dried over magnesium sulfate, filtered and concentrated to dryness.The resulting crude product was used directly in next step (20 mg, 80%).LCMS calculated for C₁₇H₁₆ClFNO₂ (M−NH₂)⁺: m/z=320.1. found: 320.1.

Step 4.3′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide

A mixture of 6-bromo-9H-purine (13 mg, 0.065 mmol),3′-(1-aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxamide(20 mg, 0.06 mmol), and N,N-diisopropylethylamine (0.021 mL, 0.12 mmol)in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₂H₂₁ClFN₆O₂(M+H)⁺: m/z=455.1. found: 455.0.

Example 631-({3′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}carbonyl)azetidine-3-carbonitrile

Step 1.3′-Acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylicacid

A mixture of methyl3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylate(1.2 g, 3.4 mmol) and 3.75 M sodium hydroxide in water (10 mL, 38 mmol)in methanol (10 mL) was stirred at room temperature overnight. Themixture was neutralized with HCl and extracted with ethyl acetate. Thecombined organic layers were washed with brine, dried over magnesiumsulfate, filtered and concentrated to dryness under reduced pressure.The residue was used directly in next step (704 mg, 61%). LCMScalculated for C₁₇H₁₅ClFO₄ (M+H)⁺: m/z=337.1. found: 337.1.

Step 2.1-[(3′-Acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-yl)carbonyl]azetidine-3-carbonitrile

To a solution of3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-carboxylicacid (70 mg, 0.2 mmol), azetidine-3-carbonitrile hydrochloride (30 mg,0.25 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.11 g, 0.25 mmol) in N,N-dimethylformamide (0.42mL) was added N,N-diisopropylethylamine (0.08 mL, 0.46 mmol). Afterbeing stirred at room temperature for 2 h, the mixture was diluted withethyl acetate, washed with water, brine, dried and concentrated todryness. The residue was purified on silica gel, eluting with 0 to 60%ethyl acetate in hexane, to give the desired product (25 mg, 30% in 3steps). LCMS calculated for C₂₁H₁₉ClFN₂O₃ (M+H)⁺: m/z=401.1. found:401.1.

Step 3.1-{[3′-(1-Aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-yl]carbonyl}azetidine-3-carbonitrile

A mixture of1-[(3′-acetyl-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-yl)carbonyl]azetidine-3-carbonitrile(25 mg, 0.062 mmol), ammonium acetate (48 mg, 0.62 mmol) and sodiumcyanoborohydride (8 mg, 0.1 mmol) in methanol (0.2 mL) and acetonitrile(0.2 mL) was heated at 65° C. overnight in a sealed tube. The mixturewas cooled to room temperature, quenched with saturated sodiumbicarbonate and extracted with dichloromethane. The combined extractswere dried over magnesium sulfate, filtered and concentrated to dryness.The resulting crude product was used directly in next step (21 mg, 84%).LCMS calculated for C₂₁H₁₉ClFN₂O₂ (M−NH₂)⁺: m/z=385.1. found: 385.1.

Step 4.1-({3′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}carbonyl)azetidine-3-carbonitrile

A mixture of 6-bromo-9H-purine (11 mg, 0.057 mmol),1-{[3′-(1-aminoethyl)-5′-chloro-3-fluoro-2′-methoxy-6′-methylbiphenyl-4-yl]carbonyl}azetidine-3-carbonitrile(21 mg, 0.052 mmol), and N,N-diisopropylethylamine (0.018 mL, 0.10 mmol)in isopropyl alcohol (0.2 mL) was heated at 90° C. under nitrogenovernight. The mixture was evaporated and the resulting mixture waspurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₆H₂₄ClFN₇O₂(M+H)⁺: m/z=520.2. found: 520.1.

Example 71N-{1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-aminetrifluoroacetate

Step 1. 1-(6-Bromo-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone

To a solution of sodium hydrogenecarbonate (0.21 g, 2.5 mmol) in water(5 mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyltrifluoromethanesulfonate (0.50 g, 1.3 mmol) in toluene (5 mL) followedby (3-fluorophenyl)boronic acid (0.21 g, 1.5 mmol) andtetrakis(triphenylphosphine)palladium(0) (75 mg, 0.065 mmol). Themixture was bubbled with N₂ for 5 min and then heated at 80° C.overnight. The reaction was diluted with water and extracted with ethylacetate. The combined organic layers were dried over sodium sulfate,concentrated and purified on silica gel (eluting with 0-20% of ethylacetate in hexanes) to give the desired product (0.40 g, 93%). LCMScalculated for C₁₅H₁₂BrClFO (M+H)⁺: m/z=341.0. found: 341.0.

Step 2.1-[4-chloro-6-(3,5-dimethylisoxazol-4-O-3′-fluoro-5-methylbiphenyl-2-yl]ethanone

To a solution of sodium hydrogenecarbonate (49 mg, 0.58 mmol) in water(1 mL) was added a solution of1-(6-bromo-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g,0.29 mmol) in toluene (1 mL) followed by3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(78 mg, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (17 mg,0.015 mmol). The reaction mixture was bubbled with N₂ for 5 min and thenheated at 80° C. overnight. The organic layer was concentrated andflashed on silica gel (eluting with 0-35% of ethyl acetate in hexanes)to afford the desired product (40 mg, 38%). LCMS calculated forC₂₀H₁₈ClFNO₂ (M+H)⁺: m/z=358.1. found: 358.1.

Step 3.1-[4-Chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethanamine

A mixture of1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethanone(40 mg, 0.11 mmol), ammonium acetate (86 mg, 1.1 mmol) and 1.0 M sodiumcyanoborohydride in tetrahydrofuran (0.28 mL, 0.28 mmol) in methanol(0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C. overnight. Themixture was cooled to room temperature, quenched with saturated sodiumbicarbonate solution and extracted with dichloromethane. The combinedorganic layers were dried over MgSO₄, filtered and concentrated to givethe desired product (35 mg, 87%). LCMS calculated for C₂₀H₂₁ClFN₂O(M+H)⁺: m/z=359.1. found: 359.1.

Step 4.N-{1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-aminetrifluoroacetate

A mixture of1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethanamine(35 mg, 0.098 mmol), 6-bromo-9H-purine (29 mg, 0.15 mmol) andN,N-diisopropylethylamine (0.034 mL, 0.20 mmol) in ethanol (0.7 mL) washeated at 100° C. for 2 hours. The residue was concentrated and purifiedon prep LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of30 mL/min) to afford the desired product as TFA salt. LCMS calculatedfor C₂₅H₂₃ClFN₆O (M+H)⁺: m/z=477.2. found: 477.1.

Example 72N-{1-[4-Chloro-3′-fluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-aminetrifluoroacetate

Step 1.1-{4-Chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′-fluoro-5-methylbiphenyl-2-yl}ethanone

To a solution of sodium hydrogenecarbonate (0.049 g, 0.58 mmol) in water(1 mL) was added a solution of1-(6-bromo-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (0.10 g,0.29 mmol) in toluene (1 mL) followed by1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.093 g, 0.35 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.017g, 0.015 mmol). The resulting mixture was bubbled with N₂ for 5 min andthen heated at 80° C. over a weekend. The organic layer was concentratedand purified on silica gel (eluting with 0-30% of ethyl acetate inhexanes) to give the desired product (37 mg, 32%). LCMS calculated forC₂₂H₂₃ClFN₂O₂ (M+H)⁺: m/z=401.1. found: 401.1.

Step 2.1-{4-Chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′-fluoro-5-methylbiphenyl-2-yl}ethanamine

A mixture of1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′-fluoro-5-methylbiphenyl-2-yl}ethanone(37 mg, 0.092 mmol), ammonium acetate (71 mg, 0.92 mmol) and 1.0 Msodium cyanoborohydride in tetrahydrofuran (0.23 mL, 0.23 mmol) inmethanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C.overnight. The mixture was cooled to room temperature, quenched withsaturated sodium bicarbonate solution, extracted with dichloromethane.The combined organic layers were dried over MgSO₄, filtered andconcentrated to give the desired product (35 mg). LCMS calculated forC₂₂H₂₆ClFN₃O (M+H)⁺: m/z=402.2. found: 402.2.

Step 3.N-{1-[4-Chloro-3′-fluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-aminetrifluoroacetate

A mixture of1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′-fluoro-5-methylbiphenyl-2-yl}ethanamine(35 mg, 0.087 mmol), 6-bromo-9H-purine (26 mg, 0.13 mmol) andN,N-diisopropylethylamine (0.030 mL, 0.17 mmol) in ethanol (0.6 mL) washeated at 100° C. overnight. The residue was concentrated and treatedwith 1.0 M hydrogen chloride in water (0.50 mL, 0.50 mmol) intetrahydrofuran (0.5 mL) overnight. The mixture was diluted with MeOHand purified on prep LCMS (XBridge C18 Column, eluting with a gradientof acetonitrile in water with 0.05% trifluoroacetic acid, at flow rateof 30 mL/min) to afford the desired product as TFA salt. LCMS calculatedfor C₂₃H₂₀ClFN₇ (M+H)⁺: m/z=448.1. found: 448.1.

Example 76N-[1-(4-Chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethyl]-9H-purin-6-aminebis(trifluoroacetate)

Step 1.1-(6-Bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone

To a solution of sodium hydrogenecarbonate (2.8 g, 34 mmol) in water (70mL) was added a solution of 6-acetyl-2-bromo-4-chloro-3-methylphenyltrifluoromethanesulfonate (6.7 g, 17 mmol) in toluene (70 mL) followedby (3,5-difluorophenyl)boronic acid (2.9 g, 19 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.98 g, 0.85 mmol). Themixture was bubbled with N₂ for 5 min and then heated at 80° C.overnight. The reaction was diluted with water and extracted with ethylacetate. The combined organic layers were dried, filtered, concentratedand purified on silica gel (eluting with 0-15% of ethyl acetate inhexanes) to give the desired product (5.6 g). LCMS calculated forC₁₅H₁₁BrClF₂O (M+H)⁺: m/z=359.0. found: 359.0.

Step 2.1-(4-Chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethanone

To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water(2 mL) was added a solution of1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20g, 0.56 mmol) in toluene (2 mL) followed by 4-pyridinylboronic Acid(0.082 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.033g, 0.029 mmol). The mixture was bubbled with N₂ for 5 min and thenheated at 80° C. overnight. The organic layer was concentrated andflashed on silica gel (eluting with 0-35% of ethyl acetate in hexanes)to afford the desired product (13 mg, 6.5%). LCMS calculated forC₂₀H₁₅ClF₂NO (M+H)⁺: m/z=358.1. found: 358.1.

Step 3.1-(4-Chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethanamine

A mixture of1-(4-chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethanone(0.013 g, 0.036 mmol), ammonium acetate (0.028 g, 0.36 mmol) and 1.0 Msodium cyanoborohydride in tetrahydrofuran (0.091 mL, 0.091 mmol) inmethanol (0.1 mL) and acetonitrile (0.1 mL) was heated at 65° C.overnight. The mixture was cooled to room temperature, quenched withsaturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were dried over MgSO₄,filtered and concentrated to give the desired product. LCMS calculatedfor C₂₀H₁₈ClF₂N₂ (M+H)⁺: m/z=359.1. found: 359.1.

Step 4.N-[1-(4-Chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethyl]-9H-purin-6-aminebis(trifluoroacetate)

A mixture of1-(4-chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethanamine(0.013 g, 0.036 mmol), 6-bromo-9H-purine (0.011 g, 0.054 mmol) andN,N-diisopropylethylamine (0.013 mL, 0.072 mmol) in ethanol (0.3 mL) washeated at 100° C. overnight. The mixture was purified on prep LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to affordthe desired product as TFA salt. LCMS calculated for C₂₅H₂₀ClF₂N₆(M+H)⁺: m/z=477.1. found: 477.1.

Example 106N-{1-[4-Chloro-3′,5′-difluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

Step 1.1-{4-Chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethanone

To a solution of sodium hydrogenecarbonate (0.093 g, 1.1 mmol) in water(2 mL) was added a solution of1-(6-bromo-4-chloro-3′,5′-difluoro-5-methylbiphenyl-2-yl)ethanone (0.20g, 0.56 mmol) in toluene (2 mL) followed by1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.18 g, 0.67 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.064g, 0.056 mmol). The mixture was bubbled with N₂ for 5 min and thenheated at 90° C. overnight. The organic layer was concentrated andflashed on silica gel (eluting with 0-20% of ethyl acetate in hexanes)to afford the desired product (94 mg, 40%). LCMS calculated forC₂₂H₂₂ClF₂N₂O₂ (M+H)⁺: m/z=419.1. found: 419.1.

Step 2.1-{4-Chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethanamine

A mixture of1-[4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethanone(0.094 g, 0.22 mmol), ammonium acetate (0.17 g, 2.2 mmol) and 1.0 Msodium cyanoborohydride in tetrahydrofuran (0.56 mL, 0.56 mmol) inmethanol (0.6 mL) and acetonitrile (0.6 mL) was heated at 65° C.overnight. The mixture was cooled to room temperature, quenched withsaturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were dried over MgSO₄,filtered and concentrated to give the desired product. LCMS calculatedfor C₂₂H₂₅ClF₂N₃O (M+H)⁺: m/z=420.2. found: 420.1.

Step 3.N-{1-[4-chloro-3′,5′-difluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

A mixture of1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluoro-5-methylbiphenyl-2-yl}ethanamine(0.074 g, 0.18 mmol), 6-bromo-9H-purine (0.053 g, 0.26 mmol) andN,N-diisopropylethylamine (0.061 mL, 0.35 mmol) in ethanol (0.6 mL) washeated at 100° C. overnight. The residue was concentrated and treatedwith 1.0 M hydrogen chloride in water (1.0 mL, 1.0 mmol) intetrahydrofuran (1 mL) overnight. The mixture was diluted with MeOH andpurified on prep LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to afford the desired product. LCMS calculated for C₂₃H₁₉ClF₂N₇(M+H)⁺: m/z=466.1. found: 466.1.

Example 108N-{1-[5-Chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine

Step 1. 6-Bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

A solution of 6-bromo-9H-purine (5.0 g, 25 mmol) and p-toluenesulfonicacid monohydrate (0.48 g, 2.5 mmol) in chloroform (100 mL) was cooled to0° C., treated with dihydropyran (3.4 mL, 38 mmol) and stirred at roomtemperature for 1 hour. The reaction mixture was washed with saturatedsodium bicarbonate, water and brine, dried with MgSO₄, filtered,concentrated and purified on silica gel (eluting with 0-50% of ethylacetate in hexanes) to give the desired product (7.0 g, 98%).

Step 2. 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol

To a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone(23 g, 83 mmol) in methanol (200 mL) was added sodium tetrahydroborate(5.0 g, 130 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hourand quenched with water (10 mL). The resulting mixture was concentratedunder reduced pressure to about 30 mL. The residue was diluted withethyl acetate, washed with water and brine, dried over MgSO₄, filteredand evaporated to yield the desired product. LCMS calculated forC₁₀H₁₁BrClO (M−OH)⁺: m/z=261.0, 263.0. found: 261.0, 263.0.

Step 3. 1-(1-Azidoethyl)-3-bromo-5-chloro-2-methoxy-4-methylbenzene

To a solution of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanol(13.4 g, 47.9 mmol) in methylene chloride (150 mL), cooled at 0° C. wasadded N,N-diisopropylethylamine (14 mL, 80 mmol) followed bymethanesulfonyl chloride (5.5 mL, 71 mmol). The mixture was stirred for1 hour at 0° C. Water (100 mL) was added while cold. The organic layerwas separated, washed with brine, dried over MgSO₄, filtered andconcentrated to dryness under reduced pressure. The resulting crudemesylate was dissolved in N,N-dimethylformamide (140 mL) and sodiumazide (6.2 g, 96 mmol) was added. The reaction was stirred at roomtemperature for 2 hours. The reaction mixture was diluted with ethylacetate and washed with saturated sodium bicarbonate solution, water andbrine, dried over MgSO₄, filtered and concentrated. The residue waspurified on silica gel (eluting with 0-30% of ethyl acetate in hexanes)to afford the desired product (12.2 g, 82%). LCMS calculated forC₁₀H₁₁BrClO (M−N₃)⁺: m/z=261.0, 263.0. found: 261.0, 263.0.

Step 4. 1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine

To a stirred solution of1-(1-azidoethyl)-3-bromo-5-chloro-2-methoxy-4-methylbenzene6-(1-azidoethyl)-2-bromo-4-chloro-3-methylphenylmethyl ether (5.6 g, 18 mmol) in tetrahydrofuran (80 mL) and water (20mL) was added 1.0 M trimethylphosphine in tetrahydrofuran (22 mL, 22mmol) at room temperature and the mixture was stirred at roomtemperature for 1 hour. The mixture was diluted with ethyl acetate,washed with saturated sodium bicarbonate solution, water and brine,dried over MgSO₄, filtered and concentrated to give the desired product(5.0 g, 98%). LCMS calculated for C₁₀H₁₁BrClO (M−NH₂)': m/z=261.0,263.0. found: 260.0, 262.9.

Step 5.N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

A mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine(5.0 g, 18 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (7.0 g,25 mmol) and N,N-diisopropylethylamine (9.4 mL, 54 mmol) in ethanol (100mL) was heated at 100° C. (flushed with nitrogen) overnight. Thereaction mixture was cooled, poured into saturated sodium bicarbonatesolution and extracted with ethyl acetate. The combined organic layerswere washed with water and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified on silica gel (eluting with 0-65%ethyl acetate in hexane) to afford the desired product. LCMS calculatedfor C₂₀H₂₄BrClN₅O₂ (M+H)⁺: m/z=480.1, 4821. found: 480.0, 482.1.

Step 6.N-{1-[5-Chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine

Into a microwave vial was addedN-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(0.046 g, 0.096 mmol), (5-fluoropyridin-3-yl)boronic acid (0.020 g, 0.14mmol), 10% sodium carbonate solution (0.23 mL, 0.23 mmol), 1,4-dioxane(0.9 mL) and tetrakis(triphenylphosphine)palladium(0) (0.011 g, 0.0096mmol). The mixture was bubbled with N₂ for 5 min and then heated at 100°C. for 2 hours. The cooled reaction was treated directly with 6.0 Mhydrogen chloride in water (0.2 mL, 1 mmol) at room temperature for ˜30min. The mixture was diluted with MeOH, filtered and purified on PrepLCMS (XBridge C18 Column, eluting with a gradient of acetonitrile inwater with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to givethe desired product. LCMS calculated for C₂₀H₁₉ClFN₆O (M+H)⁺: m/z=413.1.found: 413.1.

Example 113N-{1-[5-Chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine

Step 1. tert-Butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate

Di-tert-butyldicarbonate (10 g, 47 mmol) was added to a mixture of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine (6.6 g, 24 mmol)and triethylamine (9.9 mL, 71 mmol) in tetrahydrofuran (120 mL). After 2hours, the mixture was quenched with saturated sodium bicarbonatesolution, extracted with ethyl acetate, washed with water and brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified on silica gel (eluting with 0-5% MeOH indichloromethane) to give the desired product (6.0 g, 67%). LCMScalculated for C₁₀H₁₁BrClO (M−NHBoc)⁺: m/z=261.0, 263.0. found: 261.0,263.0. The material was separated on chiral HPLC (ChiralPak AD-H column,20×250 mm, 5 micron particle size, eluting with 2% EtOH in hexanes at 15ml/min, column loading ˜60 mg/injection) to separate the twoenantiomers.

Step 2.N-[1-(3-Bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

A mixture of tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (0.84 g,2.2 mmol) (second peak from chiral separation) was treated with 4.0 Mhydrogen chloride in dioxane (3.0 mL, 12 mmol) at room temperature for 2hours. The mixture was diluted with saturated sodium bicarbonatesolution and extracted with dichloromethane. The combined organic layerswere dried over MgSO₄, filtered and concentrated to give1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine, which wascombined with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.82 g,2.9 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (1.2mL, 6.6 mmol) in ethanol (6 mL) and heated at 100° C. overnight. Thereaction mixture was concentrated and purified on silica gel (elutingwith 0-65% ethyl acetate in hexanes) to afford the desired product. LCMScalculated for C₂₀H₂₄BrClN₅O₂ (M+H)⁺: m/z=480.1, 482.1. found: 480.0,482.0.

Step 3.N-{1-[5-Chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine

Into a microwave vial was addedN-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(0.12 g, 0.25 mmol) isolated in step 2, (5-methoxypyridin-3-yl)boronicacid (0.046 g, 0.30 mmol), 10% sodium carbonate (0.60 mL, 0.62 mmol),1,4-dioxane (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (0.017g, 0.015 mmol), the mixture was bubbled with N₂ for 5 min and thenheated at 100° C. for 2 hours. The resulting mixture was cooled to roomtemperature and then treated directly with 6.0 M hydrogen chloride inwater (0.4 mL, 2 mmol) for ˜30 minutes. The mixture was diluted withMeOH, filtered and purified on Prep LCMS (XBridge C18 Column, elutingwith a gradient of acetonitrile in water with 0.2% ammonium hydroxide,at flow rate of 60 mL/min) to give the desired single enantiomerproduct. LCMS calculated for C₂₁H₂₂ClN₆O₂ (M+H)⁺: m/z=425.1. found:425.1. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.27-7.99 (6H, m), 7.63 (1H, s), 5.71(1H, m), 3.79 (3H, s), 3.40 (3H, s), 1.94 (3H, s), 1.44 (3H, d, J=6.9Hz) ppm.

Example 117(4-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1H-pyrazol-1-yl)acetonitriletrifluoroacetate

Step 1.1-{5-Chloro-3-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-2-methoxy-4-methylphenyl}ethanone

A biphasic solution of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (0.40 g, 1.4 mmol)and1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.46 g, 1.7 mmol) in toluene (4 mL) and 10% sodium carbonate in water(3.0 mL, 2.9 mmol) was degassed under N₂.Tetrakis(triphenylphosphine)palladium(0) (83 mg, 0.072 mmol) was addedand the mixture was bubbled with N₂ for 5 min and heated at 100° C.overnight. The resulting solution was cooled to room temperature and theorganic layer was purified on silica gel (eluting with 0-40% of ethylacetate in hexanes) to give the desired product (0.22 g, 45%). LCMScalculated for C₁₇H₂₂ClN₂O₃ (M+H)⁺: m/z=337.1. found: 337.1

Step 2.1-[5-Chloro-2-methoxy-4-methyl-3-(1H-pyrazol-4-yl)phenyl]ethanone

1-{5-Chloro-3-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-2-methoxy-4-methylphenyl}ethanone(0.22 g, 0.65 mmol) was treated with 1.0 M hydrogen chloride in water(3.9 mL, 3.9 mmol) in tetrahydrofuran (4 mL) overnight. The mixture wasquenched with saturated sodium bicarbonate and extracted with ethylacetate. The organic layers were dried over MgSO₄, filtered,concentrated and purified on silica gel (eluting with 0-60% of ethylacetate in hexane) to afford the desired product (0.13 g, 75%). LCMScalculated for C₁₃H₁₄ClN₂O₂ (M+H)⁺: m/z=265.1. found: 265.0.

Step 3.[4-(3-Acetyl-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl]acetonitrile

To a solution of1-[5-chloro-2-methoxy-4-methyl-3-(1H-pyrazol-4-yl)phenyl]ethanone (0.13g, 0.49 mmol) in N,N-dimethylformamide (2 mL) was added sodium hydride(60% in oil, 0.014 g, 0.59 mmol) at 0° C. The mixture was stirred for 1hour at room temperature, followed by the addition of chloroacetonitrile(0.037 mL, 0.59 mmol) at 0° C. The reaction was stirred at roomtemperature for 1 hour, quenched with water and extracted with ethylacetate. The organic layers were dried over MgSO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedon silica gel (eluting with 0-40% of ethyl acetate in hexanes) to affordthe desired product (0.1 g, 67%). LCMS calculated for C₁₅H₁₅ClN₃O₂(M+H)⁺: m/z=304.1. found: 304.1.

Step 4.{4-[3-(1-Aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-1H-pyrazol-1-yl}acetonitrile

A mixture of[4-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-1H-pyrazol-1-yl]acetonitrile(0.10 g, 0.33 mmol), ammonium acetate (0.254 g, 3.29 mmol) and 1.0 Msodium cyanoborohydride in tetrahydrofuran (0.82 mL, 0.82 mmol) inmethanol (0.9 mL) and acetonitrile (0.9 mL) was heated at 65° C.overnight. The mixture was cooled to room temperature, quenched withsaturated sodium bicarbonate solution and extracted withdichloromethane. The combined organic layers were dried over MgSO₄ andconcentrated to give the desired product. LCMS calculated forC₁₅H₁₅ClN₃O (M−NH₂)⁺: m/z=288.1. found: 288.0.

Step 5.(4-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1H-pyrazol-1-yl)acetonitriletrifluoroacetate

A mixture of{4-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-1H-pyrazol-1-yl}acetonitrile(0.12 g, 0.39 mmol), 6-bromo-9H-purine (0.12 g, 0.59 mmol) andN,N-diisopropylethylamine (0.14 mL, 0.79 mmol) in ethanol (1 mL) washeated at 100° C. overnight. The mixture was purified on prep LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) to affordthe desired product as TFA salt. LCMS calculated for C₂₀H₂₀ClN₈O (M+H)⁺:m/z=423.1. found: 423.1. ¹H NMR (DMSO-d₆, 300 MHz) δ 9.06 (1H, br s),8.44 (2H, m), 8.00 (1H, s), 7.70 (1H, s), 7.51 (1H, s), 5.73 (1H, m),5.55 (2H, s), 3.42 (3H, s), 2.16 (3H, s), 1.53 (3H, d, J=6.9 Hz) ppm.

Compounds Synthesized

Experimental procedures for compounds below are summarized in Table 1below.

TABLE 1

Ex. No. Name R⁵ R⁴ R³ Salt Proc.¹  21 N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol- 5-yl)phenyl]ethyl}-9H-purin-6- amine ClMe

20  22 N-{1-[5-chloro-3-(3,5- dimethylisoxazol-4-yl)-2- methoxy-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  23 N-[1-[5-chloro-2-methoxy-3-(2- methoxypyrimidin-5-yl)-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  27 N-{3′-chloro-6′-methoxy-2′- methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4- yl}acetamide Cl Me

20  28 N-{1-[5-chloro-3′-fluoro-2- methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

20  29 N-[1-(5-chloro-3′,5′-difluoro-2- methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

20  30 3′-chloro-6′-methoxy-2′-methyl- 5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4- carbonitrile Cl Me

20  31 3′-chloro-N-cyclopropyl-6′- methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl- 4-carboxamide Cl Me

20  32 N-{1-[5-chloro-2-methoxy-6- methyl-4′-(methylsulfonyl)biphenyl-3- yl]ethyl}-9H-purin-6-amine Cl Me

20  33 N-{1-[3-(2-aminopyrimidin-5- yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  34 N-{1-[5-chloro-2-methoxy-3-(5- methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  35 N-[1-(3′,5-dichloro-2-methoxy- 6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

20  36 N-{1-[5-chloro-3-(5- chloropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H- purin-6-amine Cl Me

20  37 3,3′-dichloro-6′-methoxy-N,2′- dimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4- carboxamide Cl Me

20  38 N-{1-[5-chloro-2-methoxy-6- methyl-4′-(trifluoromethyl)biphenyl-3- yl]ethyl}-9H-purin-6-amine Cl Me

20  39 N-[1-(5-chloro-4′-ethoxy-3′- fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H- purin-6-amine Cl Me

20  40 3′-chloro-6′-methoxy-2′-methyl- 5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3- carbonitrile Cl Me

20  41 {3′-chloro-6′-methoxy-2′- methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4- yl}acetonitril Cl Me

20  42 N-{1-[5-chloro-2-methoxy-4′- (methoxymethyl)-6-methylbiphenyl-3-yl]ethyl}-9H- purin-6-amine Cl Me

20  43 N-{1-[5-chloro-2-methoxy-6- methyl-4′-(1H-pyrazol-1-yl)biphenyl-3-yl]ethyl}-9H- purin-6-amine Cl Me

20  44 N-{1-[5-chloro-2-methoxy-3′- (methoxymethyl)-6-methylbiphenyl-3-yl]ethyl}-9H- purin-6-amine Cl Me

20  45 N-(1-{5-chloro-2-methoxy-4- methyl-3-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3- yl]phenyl}ethyl)-9H-purin-6- amine Cl Me

20  46 {3′-chloro-6′-methoxy-2′- methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3- yl}acetonitrile Cl Me

20  47 N-[1-(3′,5,5′-trichloro-2- methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

20  48 N-{1-[5-chloro-2-methoxy-4- methyl-3-(6-morpholin-4-ylpyridin-3-yl)phenyl]ethyl}- 9H-purin-6-amine Cl Me

20  49 N-{1-[5-chloro-3-(3-fluoro-2- morpholin-4-ylpyridin-4-yl)-2-methoxy-4- methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  50² N-[1-(5-chloro-2′,5′-difluoro-2- methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

20  51 N-{1-[5-chloro-3-(6- fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H- purin-6-amine Cl Me

20  52 N-{1-[5-chloro-2-methoxy-3-(6- methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  53 5-{3-chloro-6-methoxy-2- methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl} nicotinonitrile Cl Me

20  54³ 3-(4-{3-chloro-6-methoxy-2- methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1H- pyrazol-1-yl)-3- (cyanomethyl)cyclobutanecarbonitrile Cl Me

20  55 N-{1-[5-chloro-2-methoxy-4- methyl-3-(5-methylpyridin-3-yl)phenyl]ethyl}-9H-purin-6- amine Cl Me

20  56 N-(1-{5-chloro-2-methoxy-4- methyl-3-[5-(methylsulfonyl)pyridin-3- yl]phenyl}ethyl)-9H-purin-6- amine Cl Me

20  57 N-{1-[3-(6-aminopyridin-3-yl)- 5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  58 5-{3-chloro-6-methoxy-2- methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridine- 2-carbonitrile Cl Me

20  59 N-{1-[5-chloro-3-(6- isopropoxypyridin-3-yl)-2- methoxy-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

20  64 3′-chloro-N-ethyl-3-fluoro-6′- methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl- 4-carboxamid Cl Me

63  65 3′-chloro-3-fluoro-6′-methoxy- N,N,2′-trimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl- 4-carboxamide Cl Me

63  66 N-{1-[5-chloro-3′-fluoro-2- methoxy-6-methyl-4′- (pyrrolidin-1-ylcarbonyl)biphenyl-3-yl]ethyl}- 9H-purin-6-amine Cl Me

63  67 N-{1-[5-chloro-3′-fluoro-2- methoxy-6-methyl-4′- (morpholin-4-ylcarbonyl)biphenyl-3-yl]ethyl}- 9H-purin-6-amine Cl Me

63  68 3′-chloro-3-fluoro-6′-methoxy- N,2′-dimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4- carboxamide Cl Me

63  69 1-({3′-chloro-3-fluoro-6′- methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl- 4-yl}carbonyl)piperidin-4-ol Cl Me

63  70 3′-chloro-N-cyclobutyl-3-fluoro- 6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl- 4-carboxamide Cl Me

63  84 N-{1-[5-chloro-3-(2- fluoropyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H- purin-6-amine Cl Me

2 TFA 20  85 N-[1-(3′,5-dichloro-5′-fluoro-2-methoxy-6-methylbiphenyl-3- yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20  86² N-{1-[5-chloro-2′-fluoro-2- methoxy-6-methyl-5′-(trifluoromethyl)biphenyl-3- yl]ethyl}-9H-purin-6-ami Cl Me

TFA 20  87 N-{1-[5-chloro-3-(6-fluoro-5- methylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H- purin-6-amine Cl Me

2 TFA 20  88 N-[1-(5-chloro-2-methoxy-6- methyl-4′-mopholin-4-ylbiphenyl-3-yl)ethyl]-9H-purin- 6-amine Cl Me

2 TFA 20  89 N-[1-(3′,5-dichloro-4′-fluoro-2-methoxy-6-methylbiphenyl-3- yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20  90 N-{1-[5-chloro-2-methoxy-6- methyl-4′-(trifluoromethoxy)biphenyl-3- yl]ethyl}-9H-purin-6-amine Cl Me

TFA 20  91 N-[1-(5-chloro-3′-ethoxy-2- methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20  92 N-[1-(4′,5-dichloro-3′-fluoro-2- methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20  93 N-{1-[5-chloro-4′-fluoro-2- methoxy-6-methyl-3′-(trifluoromethyl)biphenyl-3- yl]ethyl}-9H-purin-6-amine Cl Me

TFA 20  94 3′-chloro-4-fluoro-6′-methoxy- N,N,2′-trimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl- 3-carboxamide Cl Me

TFA 20  95 N-[1-(5-chloro-4′-fluoro-2,3′- dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20  96 N-[1-(5-chloro-2,3′,4′- trimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20  97 N-[1-(3′,5-dichloro-2,4′- dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20  98 N-{1-[5-chloro-3-(2- chloropyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H- purin-6-amine Cl Me

2 TFA 20  99 N-[1-(4′,5-dichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]- 9H-purin-6-amine Cl Me

TFA 20 100 N-{1-[5-chloro-3′- (dimethylamino)-2-methoxy-6-methylbiphenyl-3-yl]ethyl}-9H- purin-6-amine Cl Me

2 TFA 20 101 N-[1-(5-chloro-2,4′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]- 9H-purin-6-amine Cl Me

TFA 20 102 N-[1-(5-chloro-2,4′-dimethoxy- 3′,6-dimethylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20 103 N-[1-(5-chloro-2,3′-dimethoxy- 6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20 104 N-{3′-chloro-6′-methoxy-2′- methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3- yl}acetamide Cl Me

TFA 20 105 N-[1-(5-chloro-3′,4′-difluoro-2- methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine Cl Me

TFA 20 109 N-{1-[5-chloro-3-(5-fluoro-6- methoxypyridin-3-yl)-2-methoxy-4- methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

108 110 3′-chloro-5-fluoro-6′-methoxy- 2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3- carboxamide Cl Me

TFA 108 111 N-(1-{5-chloro-2-methoxy-4- methyl-3-[5-(morpholin-4-ylcarbonyl)pyridin-3- yl]phenyl}ethyl)-9H-purin-6- amine Cl Me

108 112 N-(5-{3-chloro-6-methoxy-2- methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2- yl)acetamide Cl Me

108 114⁴ 5-{3-chloro-6-methoxy-2- methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl} nicotinonitrile Cl Me

2 TFA 108 115⁴ N-{1-[3-(2-aminopyrimidin-5- yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin- 6-amine Cl Me

108 116⁴ N-{1-[5-chloro-2-methoxy-6- methyl-4′-(methylsulfonyl)biphenyl-3- yl]ethyl}-9H-purin-6-amine Cl Me

108 ¹Synthesized according to the experimental procedure of compoundlisted; ²Two atropic isomers isolated; ³cis- and trans-isomers isolated;⁴Single enantiomer.

Experimental procedures for compounds below are summarized in Table 2.

TABLE 2

Ex. No. Name R⁵ R⁴ R³ R^(B) Salt Proc.¹  14 N-{1-[5′- chloro-6′-methyl-4- (methyl- sulfonyl)- 1,1′:2′,1″- terphenyl-3′- yl]ethyl}-9H-purin-6-amine Cl Me

H  13  15 N-(1-{4- chloro-6-[2- (dimethyl- amino) pyrimidin- 5-yl]-5-methyl- biphenyl-2- yl}ethyl)-9H- purin-6-amine Cl Me

H  13  16 5′-chloro-N- cyclopropyl- 6′-methyl-3′- [1-(9H-purin-6-ylamino) ethyl]- 1,1′:2′,1″- terphenyl-4- carboxamide Cl Me

H  13  17 N-{1-[6-(2- amino- pyrimidin- 5-yl)-4- chloro-5- methyl-biphenyl-2- yl]ethyl}-9H- purin-6-amine Cl Me

H  13  24 5′-chloro-6′- methyl-3′-[1- (9H-purin- 6-ylamino) ethyl]-1,1′:2′,1″- terphenyl-4- carbonitrile Cl Me

H  13  25 N-{1-[4- chloro-6-(2- methoxy- pyrimidin- 5-yl)-5- methyl-biphenyl- 2-yl]ethyl}- 9H-purin-6- amine Cl Me

H  13  26 N-{5′- chloro-6′- methyl- 3′-[1-(9H- purin-6- ylamino) ethyl]-1,1′:2′,1″- terphenyl-4- yl}acetamide Cl Me

H  13  73 N-{1-[4- chloro-3′- fluoro-5- methyl-6-(1- methyl-1H-pyrazol-4-yl) biphenyl-2- yl]ethyl}-9H- purin-6-amine Cl Me

3-F TFA  71  74² N-{1-[4- chloro- 3′-fluoro-5- methyl-6-(1- methyl-1H-pyrazol-5-yl) biphenyl-2- yl]ethyl}-9H- purin-6-amine Cl Me

3-F TFA  71  75² N-{1-[4- chloro-3′- fluoro-5- methyl-6-(1,3,5-trimethyl- 1H-pyrazol-4- yl)biphenyl-2- yl]ethyl}-9H- purin-6-amineCl Me

3-F TFA  71  77 N-{1-[4- chloro-6-(3, 5-dimethyl- isoxazol-4- yl)-3′,5′-difluoro-5- methyl- biphenyl-2- yl]ethyl}-9H- purin-6-amine Cl Me

3,5- diF TFA  76  78 N-[1-(4- chloro-3′,5′- difluoro- 5-methyl-6-pyridin-3- ylbiphenyl-2- yl)ethyl]-9H- purin-6-amine Cl Me

3,5- diF 2 TFA  76  79 5′-chloro- 3″,5″- difluoro-6′- methyl-3′-[1-(9H-purin-6- ylamino) ethyl]- 1,1′:2′,1″- terphenyl-4- carbonitrile ClMe

3,5- diF TFA  76  80 N-{1-[4- chloro-6-(2,6- difluoro- pyridin-4-yl)-3′,5′-difluoro- 5-methyl- biphenyl-2- yl]ethyl}-9H- purin-6-amine Cl Me

3,5- diF 2 TFA 76  81 N-[1-(4- chloro-3′,5′- difluoro- 5-methyl-6-pyrimidin-5- ylbiphenyl-2- yl)ethyl]-9H- purin-6-amine Cl Me

3,5- diF 2 TFA  76  82 N-{1-[4- chloro-3′,5′- difluoro-6- (2-methoxy-pyrimidin-5- yl)-5-methyl- biphenyl-2- yl]ethyl}-9H- purin-6- amine ClMe

3,5- diF 2 TFA  76  83 N-{5′- chloro- 3″,5″- difluoro- 6′-methyl-3′-[1-(9H- purin-6- ylamino) ethyl]- 1,1′:2′,1″- terphenyl- 4-yl}acetamide Cl Me

3,5- diF TFA  76 107 N-{1-[4- chloro-6- (3,5- dimethyl- 1H-pyrazol-4-yl)-3′,5′- difluoro-5- methyl- biphenyl- 2-yl]ethyl}- 9H-purin-6-amine Cl Me

3,5- diF TFA 106 ¹Synthesized according to the experimental procedure ofcompound listed; ²Two atropic isomers isolated.Analytical Data

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds of the Examples above is provided below in Table3.

TABLE 3 Ex. MS No. [M + H]⁺ Solvent MHz ¹H NMR Spectra 14 518.2 — — — 15485.2 — — — 16 523.2 — — — 17 457.0 — — — 21 398.1 — — — 22 413.1DMSO-d₆ 400 12.87 (1H, br s), 8.12~8.09 (3H, m), 7.67 (1H, m), 5.75 (1H,m), 3.48 (1.5H, s), 3.43 (1.5H, s), 2.21 (1.5H, s), 2.19 (1.5H, s), 2.01(3H, s), 2.00 (1.5H, s), 1.98 (1.5H, s), 1.57 (3H, m) ppm. 23 426.1 — —— 24 465.1 — — — 25 472.2 DMSO-d₆ 400 12.85 (1H, br s), 8.32 (1H, d, J =3.2 Hz), 8.17 (1H, m), 8.15 (1H, s), 8.11 (1H, s), 8.08 (1H, d, J = 2.8Hz), 7.83 (1H, s), 7.44 (1H, d, J = 6.0 Hz), 7.29 (1H, t, J = 6.8 Hz),7.19 (2H, m), 7.01 (1H, d, J = 7.2 Hz), 5.05 (1H, m), 3.79 (3H, s), 2.03(3H, s), 1.29 (3H, d, J = 6.8 Hz) ppm. 26 497.1 — — — 27 451.2 — — — 28412.1 — — — 29 430.1 — — — 30 419.1 — — — 31 477.1 — — — 32 472.1 — — —33 411.1 — — — 34 425.1 — — — 35 428.1 — — — 36 429.0 DMSO-d₆ 400 12.83(1H, br s), 8.67 (1H, s), 8.52 (0.5H, s), 8.42 (1H, s), 8.10 (4H, m),7.69 (1H, s), 5.75 (1H, m), 3.44 (3H, s), 2.00 (3H, s), 1.48 (1H, d, J =7.2 Hz) ppm. 37 485.1 — — — 38 462.1 — — — 39 456.2 — — — 40 419.1DMSO-d₆ 400 12.93 (1H, s), 8.23 (1H, m), 8.11 (1H, m), 7.87 (1H, m),7.69~7.60 (4H, m), 5.74 (1H, m), 3.39 (3H, s), 1.97 (3H, s), 1.48 (3H,d, J = 4.4 Hz) ppm. 41 433.1 — — — 42 438.1 — — — 43 460.1 — — — 44438.1 — — — 45 495.2 — — — 46 433.1 — — — 47 462.0 — — — 48 480.1 — — —49 498.1 DMSO-d₆ 400 12.94 (1H, br s), 8.22~8.09 (4H, m), 7.71 (1H, m),6.93 (0.5H, dd, J = 4.8 and 4.4 Hz), 6.82 (0.5H, dd, J = 4.8 and 4.4Hz), 5.37 (1H, m), 3.72 (4H, m), 3.54 (1.5H, s), 3.51 (1.5H, s), 3.36(4H, m), 1.99 (1.5H, s), 1.97 (1.5H, s), 1.47 (3H, m) ppm. 50 430.1 — —— 51 413.1 DMSO-d₆ 400 12.91 (1H, br s), 8.22 (1H, s), 8.14~7.92 (3H,m), 8.03 (0.5H, m), 7.92 (0.5H, m), 7.68 (1H, s), 7.29 (1H, m), 5.73(1H, m), 3.42 (3H, s), 2.00 (3H, s), 1.48 (3H, d, J = 6.8 Hz) ppm. 52425.1 DMSO-d₆ 400 12.88 (1H, br s), 8.17~8.00 (4H, m), 7.64~7.60 (2H,m), 6.86 (1H, d, J = 8.4 Hz), 5.69 (1H, m), 3.84 (3H, s), 3.36 (3H, s),1.96 (3H, s), 1.43 (3H, d, J = 6.8 Hz) ppm. 53 420.1 — — — 54 502.1 — —— 55 409.0 — — — 56 473.0 — — — 57 410.1 — — — 58 420.1 — — — 59 453.1DMSO-d₆ 300 8.19 (1H, m), 8.14 (1H, s), 8.12 (1H, s), 8.04 (1H, m), 7.62(2H, m), 6.82 (1H, d, J = 8.4 Hz), 5.73 (1H, m), 5.28 (1H, m), 3.41 (3H,s), 2.02 (3H, s), 1.48 (3H, d, J = 6.6 Hz), 1.31 (6H, d, J = 6.0 Hz)ppm. 64 483.1 — — — 65 483.1 — — — 67 509.2 — — — 68 525.2 — — — 69469.1 — — — 70 539.2 — — — 71 509.1 — — — 73 462.0 — — — 74 462.2 — — —75 490.0 — — — 77 495.1 — — — 78 477.1 — — — 79 501.1 — — — 80 513.1 — —— 81 478.0 — — — 82 508.1 — — — 83 533.2 — — — 84 413.1 DMSO-d₆ 300 9.19(1H, br s), 8.47 (2H, m), 8.34 (1H, d, J = 5.1 Hz), 7.65 (1H, s), 7.33(1H, m), 7.22 (1H, m), 5.75 (1H, m), 3.42 (3H, s), 2.01 (3H, s), 1.55(3H, d, J = 6.9 Hz) ppm. 85 446.1 — — — 86 480.1 — — — 87 427.1 — — — 88479.2 — — — 89 446.1 — — — 90 478.1 — — — 91 438.1 — — — 92 446.0 — — —93 480.1 — — — 94 483.2 DMSO-d₆ 300 9.24 (1H, br s), 8.49 (2H, m), 7.57(1H, s), 7.39 (2H, m), 7.28 (1H, m), 5.75 (1H, m), 3.34 (3H, s), 2.99(1.5H, s), 2.98 (1.5 H, s), 2.87 (1.5 H, s), 2.86 (1.5 H, s), 2.02 (3H,s), 1.55 (3H, d, J = 6.9 Hz) ppm. 95 442.1 — — — 96 454.1 — — — 97 458.1— — — 98 429.1 DMSO-d₆ 300 9.11 (1H, br s), 8.51 (1H, d, J = 4.8 Hz),8.45 (2H, m), 7.65 (1H, s), 7.54 (1H, m), 7.41 (1H, m), 5.74 (1H, m),3.42 (3H, s), 2.01 (3H, s), 1.54 (3H, d, J = 7.2 Hz) ppm. 99 428.0 — — —100 437.2 — — — 101 424.1 — — — 102 438.1 — — — 103 424.1 — — — 104451.1 — — — 105 430.0 — — — 107 494.1 — — — 109 443.1 DMSO-d₆ 300 8.17(1H, m), 8.10 (1H, m), 8.08 (1H, s), 7.86 (1H, m), 7.78 (1H, m), 7.61(1H, s), 5.70 (1H, m), 3.94 (3H, s), 3.40 (3H, s), 1.98 (3H, s), 1.43(3H, d, J = 6.6 Hz) ppm. 110 455.1 DMSO-d₆ 300 8.80 (1H, br s), 8.35(2H, m), 8.08 (1H, m), 7.72 (1H, m), 7.65~7.59 (3H, m) 7.43 (0.5H, m),7.35 (0.5 H, m), 5.75 (1H, m), 3.40 (1.5H, s), 3.38 (1.5H, s), 2.00 (3H,s), 1.53 (3H, d, J = 6.6 Hz) ppm. 111 508.1 DMSO-d₆ 300 8.60 (1H, s),8.57 (0.5H, m), 8.49 (0.5H, m), 8.16~8.07 (3H, m), 7.84 (0.5H, m), 7.73(0.5H, m), 7.64 (1H, m), 5.67 (1H, m), 3.58 (4H, m), 3.35 (3H, s), 3.29(4H, m), 1.99 (1.5H, s), 1.96 (1.5H, s), 1.44 (3H, d, J = 6.9 Hz) ppm.112 452.1 DMSO-d₆ 300 10.55 (1H, s), 8.15 (2H, m), 8.12 (1H, s), 8.09(1H, s), 8.06 (1H, s), 7.70 (1H, m), 7.59 (1H, m), 5.69 (1H, m), 3.37(3H, s), 2.06 (3H, s), 1.97 (3H, s), 1.43 (3H, d, J = 6.6 Hz) ppm. 114420.0 DMSO-d₆ 300 12.68 (1H, br s), 9.07 (1H, d, J = 0.9 Hz), 8.21~7.99(5H, m), 7.72 (1H, s), 5.73 (1H, m), 3.42 (3H, s), 2.00 (3H, s), 1.49(3H, d, J = 7.2 Hz) ppm. 115 411.1 DMSO-d₆ 300 12.71 (1H, br s),8.12~8.06 (4H, m), 7.55 (1H, s), 6.73 (2H, s), 5.68 (1H, m), 3.43 (3H,s), 2.03 (3H, s), 1.43 (3H, d, J = 7.2 Hz) ppm. 116 472.0 DMSO-d₆ 3008.22 (1H, m), 8.15 (1H, s), 8.12 (1H, s), 8.01 (2H, d, J = 9.0 Hz), 7.67(1H, s), 7.62 (1H, m), 7.55 ((1H, m), 5.73 (1H, m), 3.40 (3H, s), 3.29(3H, s), 1.97 (3H, s), 1.49 (3H, d, J = 6.9 Hz) ppm.

Example 118N-{1-[5-Fluoro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine

Step 1. 4-Fluoro-3-methylphenyl acetate

A solution of 4-fluoro-3-methylphenol (3.0 g, 23 mmol) and methylenechloride (96 mL) was cooled to 0° C. in an ice bath. Triethylamine (4.9mL, 35 mmol) was introduced to the solution followed by dropwiseaddition of acetyl chloride (2.3 mL, 33 mmol). The ice bath was removedand the mixture was stirred for 1 hour. The mixture was then extractedwith methylene chloride and washed with 0.5 N HCl, saturated sodiumbicarbonate and brine. The extracts were dried over sodium sulfate,filtered and evaporated to give 4-fluoro-3-methylphenyl acetate (3.9 g,quantitative). ¹H NMR (400 MHz, CDCl₃): δ 7.00 (m, 1H), 6.87 (m, 2H),2.29 (m, 6H).

Step 2. 1-(5-Fluoro-2-hydroxy-4-methylphenyl)ethanone

A suspension of 4-fluoro-3-methylphenyl acetate (3.9 g, 23 mmol) inboron trifluoride acetic acid complex (47 mL, 340 mmol) was heated at155° C. for 14 hours. The mixture was then cooled to 0° C. in an icebath and ice was added directly to the mixture. The ice bath wassubsequently removed and the mixture stirred until the ice added to themixture was dissolved. The mixture was then diluted with cold water andfiltered. The isolated rust-colored solid was washed with cold water andallowed to dry in air to give1-(5-Fluoro-2-hydroxy-4-methylphenyl)ethanone (3.2 g, 81%). ¹H NMR (400MHz, CDCl₃): δ 11.98 (s, 1H), 7.34 (m, 1H), 6.80 (m, 1H), 2.60 (s, 3H),2.28 (s, 3H).

Step 3. 1-(3-Bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone

To a solution of 1-(5-fluoro-2-hydroxy-4-methylphenyl)ethanone (2.2 g,13 mmol) and acetic acid (20 mL, 400 mmol) was added N-bromosuccinimide(2.8 g, 16 mmol). The resulting mixture was stirred at room temperaturefor 18 hours. The reaction mixture was then concentrated in vacuo,neutralized with saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with brine, dried oversodium sulfate, filtered and concentrated to dryness under reducedpressure. Purification on silica gel with ethyl acetate/hexanes (0-50%)gave 1-(3-Bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone (2.3 g, 71%).¹H NMR (400 MHz, CDCl₃): δ 12.80 (s, 1H), 7.40 (m, 1H), 2.60 (s, 3H),2.40 (s, 3H).

Step 4. 1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone

To a mixture of 1-(3-bromo-5-fluoro-2-hydroxy-4-methylphenyl)ethanone(0.3 g, 1 mmol) and potassium carbonate (0.43 g, 3.1 mmol) was addedN,N-dimethylformamide (1 mL) and methyl iodide (0.17 mL, 2.7 mmol) withstirring. The resulting mixture was then heated at 60° C. for 1 hour.The mixture was diluted with water and extracted with ethyl acetate. Thecombined extracts were washed with brine, dried over sodium sulfate, andevaporated to dryness. The isolated residue was purified on silica gel,eluting with ethyl acetate/hexanes (0 to 20%) to yield1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone (0.24 g, 80%).LCMS calculated for C₁₀H₁₁BrFO₂ (M+H)⁺: m/z=261.0, 263.0. Found: 260.9,262.9. ¹H NMR (400 MHz, CDCl₃): δ 7.35 (m, 1H), 3.82 (s, 3H), 2.61 (s,3H), 2.39 (s, 3H).

Step 5. 1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanaminetrifluoroacetate

A mixture of 1-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanone (140mg, 0.55 mmol) and ammonium acetate (640 mg, 8.3 mmol) in acetonitrile(1.3 mL) and methanol (1.3 mL) was heated at 65° C. for 1 hour. Sodiumcyanoborohydride (87 mg, 1.4 mmol) was added and the resulting mixturewas heated at 65° C. for 3 hours. Purification by preparative LCMS (pH2) RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrilein water with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanamine trifluoroacetate(150 mg, 70%). LCMS calculated for C₁₀H₁₁BrFO (M−NH₂)⁺: m/z=245.0,247.0. Found: 244.9, 246.9.

Step 6.N-[1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

A mixture of 1-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethanaminetrifluoroacetate (130 mg, 0.35 mmol),6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (150 mg, 0.53 mmol, fromExample 108, Step 1), N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) andethanol (2.0 mL) was heated at 95° C. for 1 hour. The resulting mixturewas diluted with methanol and purified by preparative LCMS (pH 10)RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile inwater with 0.2% ammonium hydroxide, at flow rate of 60 mL/min) to affordN-[1-(3-Bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(40 mg, 47%). LCMS calculated for C₂₀H₂₄BrFN₅O₂ (M+H)⁺: m/z=464.0,466.0. Found: 464.1, 466.1.

Step 7.N-{1-[5-Fluoro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine

N-[1-(3-bromo-5-fluoro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(21 mg, 0.044 mmol), [4-(methylsulfonyl)phenyl]boronic acid (13 mg,0.066 mmol), potassium carbonate (15 mg, 0.11 mmol), water (0.2 mL), and1,4-dioxane (0.40 mL) were added to a microwave vial. The mixture wasdegassed under nitrogen for 5 minutes.Tetrakis(triphenylphosphine)palladium(0) (5.1 mg, 4.4 μmol) was added tothe mixture and the vial was then sealed and bubbled under nitrogen for5 minutes. The mixture was heated at 80° C. overnight. The cooledreaction mixture was then treated with 4.0 M hydrogen chloride in water(0.5 mL, 2 mmol) and was stirred at room temperature for 30 minutes.Purification by preparative LCMS (pH 10) RP-HPLC (XBridge C18 Column,eluting with a gradient of acetonitrile in water with 0.2% ammoniumhydroxide, at flow rate of 60 mL/min) affordedN-{1-[5-Fluoro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine(13 mg, 66%). LCMS calculated for C₂₂H₂₃FN₅O₃S (M+H)⁺: m/z=456.1. Found:456.0.

Experimental procedures for compounds of Examples 118-123 are summarizedin Table 4 below.

TABLE 4

Ex. No. Name R⁵ R⁴ R³ Salt Proc.¹ 118 N-{1-[5-fluoro- 2-methoxy-6-methyl-4′- (methylsulfonyl) biphenyl-3- yl]ethyl}-9H- purin-6-amine F Me

Parent above 119 N-[1-(3′-ethoxy- 5-fluoro-2- methoxy-6- methylbiphenyl-3-yl)ethyl]-9H- purin-6-amine F Me

Parent 118 120 N-cyclopropyl- 3′-fluoro-6′- methyl-2′- methyl-5′-[1-(9H-purin-6- ylamino)ethyl] biphenyl-4- carboxamide F Me

Parent 118 121 N-{1-[5-fluoro- 2-methoxy-4- methyl-3-(1- methyl-1H-pyrazol-4-yl) phenyl]ethyl}- 9H-purin-6- amine F Me

Parent 118 122 N-{1-[5-fluoro- 2-methoxy-4- methyl-3-(1- methyl-1H-pyrazol-5-yl) phenyl]ethyl}- 9H-purin-6- amine F Me

Parent 118 123 N-{1-[3-(2- aminopyrimidin- 5-yl)-5-fluoro- 2-methoxy-4-methylphenyl] ethyl}-9H- purin-6-amine F Me

Parent 118 ¹Synthesized according to the experimental procedure ofcompound listed.Analytical Data

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds of Examples 118-123 is provided below in Table 5.

TABLE 5 Ex. MS No. [M + H]⁺ Solvent MHz ¹H NMR Spectra 118 456.0 DMSO-500 δ 8.12 (m, 2 H), 8.03 (m, 2 H), d₆ 7.60 (br s, 1 H), 7.40 (m, 1 H),5.80 (br s, 3 H), 3.40 (s, 3 H), 3.25 (s, 3 H), 1.85 (s, 3 H), 1.50 (m,3 H). 119 422.2 DMSO- 500 δ δ 8.12 (m, 2 H), 8.00 (br s, 1 H), d₆ 7.33(m, 2 H), 6.95 (m, 1 H), 6.80 (m, 2 H), 5.80 (br s, 1 H), 4.03 (m, 2 H),3.40 (s, 3 H), 1.85 (s, 3 H), 1.50 (m, 3 H), 1.31 (m, 3 H). 120 461.2DMSO- 500 δ 8.44 (m, 1 H), 8.12 (m, 2 H), d₆ 8.02 (br s, 1 H), 7.90 (m 1H), 7.38 (m, 2 H), 5.80 (br s, 1 H), 3.40 (s, 3 H), 2.89 (m, 1 H), 1.85(s, 3 H), 1.50 (m, 3 H), 0.70 (m, 2 H), 0.59 (m, 2 H). 121 382.1 DMSO-500 δ 8.12 (m, 2 H), 8.00 (br s, 1 H), d₆ 7.83 (s, 1 H), 7.51 (s, 1 H),7.20 (m, 1 H), 5.80 (br s, 1 H), 3.89 (s, 3 H), 3.45 (s, 3 H), 2.01 (s,3 H), 1.47 (m, 3 H). 122 382.2 DMSO- 500 δ 8.12 (m, 2 H), 8.00 (br s, 1H), d₆ 7.53 (m, 1 H), 7.39 (m, 1 H), 6.40 (m, 1 H), 5.80 (br s, 1 H),3.56 (s, 3 H), 3.50 (s, 3 H), 1.85 (s, 3 H), 1.48 (m, 3 H). 123 395.1DMSO- 500 δ 8.20 (s, 1 H), 8.12 (m, 2 H), d₆ 8.02 (br s, 1 H), 7.32 (m,1 H), 6.73 (s, 1 H), 5.80 (br s, 1 H), 3.43 (s, 3 H), 1.98 (s, 3 H),1.48 (m, 3 H).

Example 124N-{1-[4-Chloro-3′,5′-difluoro-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

Step A: 2-Acetyl-6-bromo-4-chlorophenyl trifluoromethanesulfonate

The desired compound was prepared according to the procedure of Example1, step 3, using 1-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone as thestarting material in 97% yield. LCMS for C₉H₆BrClF₃O₄S (M+H)⁺:m/z=380.9, 382.9. Found: 380.8, 382.9.

Step B: 1-(6-Bromo-4-chloro-3′,5′-difluorobiphenyl-2-yl)ethanone

A solution of sodium hydrogenecarbonate (2.0 g, 23 mmol) in water (50mL) was treated with a solution of 2-acetyl-6-bromo-4-chlorophenyltrifluoromethanesulfonate (4.5 g, 12 mmol) in toluene (50 mL) followedby (3,5-difluorophenyl)boronic acid (2.0 g, 13 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.67 g, 0.58 mmol). Thereaction mixture was degassed with nitrogen for 5 min and heated at 80°C. overnight. The reaction mixture was diluted with water and extractedwith ethyl acetate (2×100 mL). The combined organic layers were washedwith sodium bicarbonate, water, and brine, dried with sodium sulfate,filtered, and concentrated to a crude residue. Purification by flashcolumn chromatography using ethyl acetate in hexanes (0%-10%) gave thedesired product (3.7 g, 82%). LCMS for C₁₄H₉BrClF₂O (M+H)⁺: m/z=344.9,346.9. Found: 344.9, 346.8.

Step C:1-{4-Chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanone

A solution of 1-(6-bromo-4-chloro-3′,5′-difluorobiphenyl-2-yl)ethanone(300 mg, 0.87 mmol),1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(250 mg, 0.96 mmol), and sodium carbonate (280 mg, 2.6 mmol) in1,4-dioxane (3.0 mL, 38 mmol) was degassed with nitrogen 5 minutes,treated with tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087mmol) degassed with additional nitrogen for 5 mins, and heated at 80° C.overnight. The reaction mixture was diluted with water and extractedwith ethyl acetate (2×60 mL). The combined organic layers were washedwith water and brine, dried with sodium sulfate, filtered, andconcentrated to a crude residue. Purification via preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave thedesired product (190 mg, 54%).

Step D:1-{4-Chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanamine

A solution of1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanone(190 mg, 0.47 mmol), ammonium acetate (360 mg, 4.7 mmol) in methanol (2mL) and acetonitrile (2 mL) was heated at 65° C. for 3 hours. Thereaction mixture was quenched with acetic acid (˜100 uL) and poured intosodium bicarbonate (50 mL). This mixture was extracted withdichloromethane (3×60 mL) and the combined organic layers were washedwith brine, dried with sodium sulfate, filtered, and concentrated to acrude residue. Purification via preparative LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) gave the desired product (60 mg,32%). LCMS for C₂₁H₂₃ClF₂N₃O (M+H)⁺: m/z=406.1. Found: 406.1.

Step E:N-{1-[4-Chloro-3′,5′-difluoro-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine

A solution of1-{4-chloro-6-[1-(1-ethoxyethyl)-1H-pyrazol-4-yl]-3′,5′-difluorobiphenyl-2-yl}ethanamine(60 mg, 0.15 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (63mg, 0.22 mmol, from Example 108, Step 1), and N,N-diisopropylethylamine(77 μL, 0.44 mmol) in ethanol (2.8 mL) was heated in the microwave at130° C. for 30 minutes. Alternatively, this reaction can be heated at90° C. overnight on the benchtop. The reaction mixture was cooled toroom temperature, treated with 6 M Hydrogen chloride in water (0.49 mL,3.0 mmol), and stirred for 30 minutes. The reaction mixture was dilutedslightly with methanol, filtered, and directly purified via preparativeLCMS (XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to givethe desired product (29 mg, 43%). LCMS for C₂₂H₁₇ClF₂N₇ (M+H)⁺:m/z=452.1. Found: 452.0; ¹H NMR (300 MHz, DMSO-d₆): δ 12.8 (br s, 1H),8.32-8.23 (m, 1H), 8.11 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 7.46 (s,1H), 7.36-7.23 (m, 3H), 7.09-7.01 (m, 1H), 6.96 (d, J=8.5 Hz, 1H),5.09-4.96 (m, 1H), 1.34 (d, J=6.7 Hz, 3H).

Example 125N-{1-[5-Chloro-3-(5-chloropyridin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine

Step A: 1-(3-Bromo-5-chloro-2-methoxyphenyl)ethanone

A solution of 1-(3-bromo-5-chloro-2-hydroxyphenyl)ethanone (5.0 g, 20mmol) in N,N-dimethylformamide (40 mL) was treated with potassiumcarbonate (5.5 g, 40 mmol) followed by methyl iodide (1.9 mL, 30 mmol)and heated at 60° C. overnight. The reaction mixture was diluted withwater (300 mL) and extracted with ethyl acetate (2×150 mL). The organiclayers were washed with water (3×100 mL) and brine, dried with sodiumsulfate, filtered, and concentrated to give the crude product.Purification by flash column chromatography using ethyl acetate inhexanes (0%-5%-25%) gave the desired product (5.1 g, 96%). LCMS forC₉H₉BrClO₂ (M+H)⁺: m/z=262.9, 264.9. Found: 262.9, 264.9.

Step B: 1-(3-Bromo-5-chloro-2-methoxyphenyl)ethanamine

The desired compound was prepared according to the procedure of Example124, step D, using 1-(3-bromo-5-chloro-2-methoxyphenyl)ethanone as thestarting material in 56% yield. LCMS for C₉H₁₂BrClNO (M+H)⁺: m/z=264.0,266.0. Found: 263.9, 265.9.

Step C:N-[1-(3-Bromo-5-chloro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

A solution of 1-(3-bromo-5-chloro-2-methoxyphenyl)ethanamine (2.2 g, 8.5mmol) in ethanol (69 mL), was treated with6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.6 g, 13 mmol, fromExample 108, Step 1) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) andheated at reflux overnight. The reaction mixture was cooled, poured intosodium bicarbonate (150 mL) and extracted with ethyl acetate (2×150 mL).The combined organic layers were washed with water and brine, dried withsodium sulfate, filtered, and concentrated to a crude residue.Purification by flash column chromatography using acetonitrile indichloromethane (5%-10%) and then ethyl acetate in hexanes (60%-100%)gave the desired product (3.9 g, 98%). LCMS for C₁₉H₂₂BrClN₅O₂ (M+H)⁺:m/z=466.1, 468.1. Found: 466.0, 468.0.

Step D:N-{1-[5-Chloro-3-(5-chloropyridin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine

A solution ofN-[1-(3-bromo-5-chloro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(45 mg, 0.096 mmol) and (5-chloropyridin-3-yl)boronic acid (23 mg, 0.15mmol) in water (0.5 mL) and 1,4-dioxane (1 mL) was treated withpotassium carbonate (33 mg, 0.24 mmol) andtetrakis(triphenylphosphine)palladium(0) (11 mg, 9.6 mmol). The reactionmixture was degassed with nitrogen for 5 min and heated at 80° C.overnight. The reaction mixture was cooled treated directly with 6 Mhydrogen chloride in water (170 μL, 1.0 mmol) and stirred at roomtemperature for ˜30 minutes. The reaction mixture was diluted slightlywith methanol, filtered, and directly purified via preparative LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to givethe desired product (6 mg, 15%). LCMS for C₁₉H₁₇Cl₂N₆O (M+H)⁺:m/z=415.1. Found: 415.0; ¹H NMR (300 MHz, DMSO-d₆): δ 8.72 (d, J=1.8 Hz,1H), 8.66 (d, J=2.3 Hz, 1H), 8.20-8.09 (m, 4H), 7.65 (d, J=2.1 Hz, 1H),7.40 (d, J=2.6 Hz, 1H), 5.91-5.71 (m, 1H), 3.52 (s, 3H), 1.51 (d, J=7.0Hz, 3H).

Example 126N-{1-[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethyl}-9H-purin-6-amine

Step A:1-[3-Bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethanone

A solution of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (34mg, 0.13 mmol), triphenylphosphine (47 mg, 0.18 mmol), and4-morpholineethanol (23 μL, 0.19 mmol) in tetrahydrofuran (0.38 mL, 4.6mmol) at −10° C. was treated with diisopropyl azodicarboxylate (35 μL,0.18 mmol) dropwise and stirred at −10° C. for 15 min and warmed to 20°C. for 30 minutes. The reaction mixture was concentrated, diluted withethyl acetate (5 mL), and washed with water and brine, dried withmagnesium sulfate, filtered, and concentrated to a crude oil.Purification by flash column chromatography using ethyl acetate inhexanes (0%-60%) gave the desired product (15 mg, 31%). LCMS forC₁₅H₂₀BrClNO₃ (M+H)⁺: m/z=376.0, 378.0. Found: 375.9, 378.0.

Step B:1-[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethanone

The desired compound was prepared according to the procedure of Example124, step C, using1-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethanoneand cesium carbonate (instead of sodium carbonate) as the startingmaterials in 62% yield. LCMS for C₂₀H₂₄ClN₂O₃ (M+H)⁺: m/z=375.1. Found:375.1.

Step C:1-[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethanamine

The desired compound was prepared according to the procedure of Example124, step D, using1-[5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethanoneas the starting material in 98% yield. LCMS for C₂₀H₂₇ClN₃O₂ (M+H)⁺:m/z=376.2. Found: 376.1.

Step D:N-{1-[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethyl}-9H-purin-6-amine

The desired compound was prepared according to the procedure of Example124, step E, using1-[5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethanamineas the starting material in 12% yield. LCMS for C₂₅H₂₉ClN₇O₂ (M+H)⁺:m/z=494.2. Found: 494.2; ¹H NMR (300 MHz, DMSO-d₆): δ 12.9 (s, 1H), 8.65(d, J=5.0 Hz, 2H), 8.26-8.15 (m, 1H), 8.12 (s, 1H), 8.06 (s, 1H), 7.68(s, 1H), 7.47-7.29 (m, 2H), 5.86-5.72 (m, 1H), 4.08-4.00 (m, 1H),3.41-3.37 (m, 4H), 2.31-2.28 (m, 2H), 2.21-2.14 (m, 2H) 2.10-2.04 (m,2H), 1.96 (s, 3H), 1.48 (d, J=7.0 Hz, 3H).

Example 127N-[1-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethyl]-9H-purin-6-amine

Step A. 1-(5-Chloro-2-hydroxy-4-methyl-3-pyridin-4-ylphenyl)ethanone

A solution of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (2.6g, 9.9 mmol), 4-pyridinylboronic acid (1.6 g, 13 mmol), and potassiumcarbonate (5.5 g, 40 mmol) in 1,2-dimethoxyethane (48 mL) and water (24mL) was degassed with nitrogen and treated with triphenylphosphine (260mg, 0.99 mmol) and palladium acetate (0.22 g, 0.99 mmol). The reactionmixture was degassed with nitrogen for 5 min and heated at 90° C. for 20hours. The reaction mixture was cooled to room temperature, concentratedto remove most of the DME, diluted with ethyl acetate (200 ml) and water(100 ml), and filtered over celite. The aqueous layer was separated andextracted with ethyl acetate (100 mL). The combined organic layers werewashed with brine (100 ml), dried over sodium sulfate, filtered, andconcentrated to a crude brown foam. Purification by flash columnchromatography using ethyl acetate in hexanes (0%-60%) gave the desiredproduct (1.2 g, 45%). LCMS for C₁₄H₁₃ClNO₂ (M+H)⁺: m/z=262.1. Found:262.0.

Step B: 6-Acetyl-4-chloro-3-methyl-2-pyridin-4-ylphenyltrifluoromethanesulfonate

The desired compound was prepared according to the procedure of Example1, step 3, using1-(5-chloro-2-hydroxy-4-methyl-3-pyridin-4-ylphenyl)ethanone as thestarting material in 81% yield. LCMS for C₁₅H₁₂ClF₃NO₄S (M+H)⁺:m/z=394.0. Found: 393.9.

Step C: 1-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethanone

A solution of 6-acetyl-4-chloro-3-methyl-2-pyridin-4-ylphenyltrifluoromethanesulfonate (0.40 g, 1.0 mmol) in 1,4-dioxane (10 mL, 130mmol) was degassed with nitrogen and treated with[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex withdichloromethane (1:1) (41 mg, 0.051 mmol). The reaction mixture wasdegassed with nitrogen for 5 minutes, treated with 2.0 M dimethylzinc intoluene (0.76 mL, 1.5 mmol), and heated at 70° C. for 1.5 hours. Thereaction mixture was cooled to room temperature diluted with ethylacetate and water and filtered over celite to remove solids. The ethylacetate layer was separated, washed with brine, dried over sodiumsulfate, filtered, and concentrated to a crude brown gum. Purificationby flash column chromatography using ethyl acetate in hexanes (0%-20%)gave the desired product (0.18 g, 69%). LCMS for C₁₅H₁₅ClNO (M+H)⁺:m/z=260.1. Found: 260.1.

Step D: 1-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethanamine

The desired compound was prepared according to the procedure of Example124, step D, using1-(5-chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethanone as the startingmaterial in 40% yield. LCMS for C₁₅H₁₈ClN₂ (M+H)⁺: m/z=261.1. Found:261.0.

Step E:N-[1-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethyl]-9H-purin-6-amine

The desired compound was prepared according to the procedure of Example124, step E, using1-(5-chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethanamine as the startingmaterial in 32% yield. LCMS for C₂₀H₂₀ClN₆ (M+H)⁺: m/z=379.1. Found:379.1; ¹H NMR (400 MHz, DMSO-d₆): δ 12.9 (br s, 1H), 8.67-8.64 (m, 2H),8.32-8.24 (m, 1H), 8.12 (s, 2H), 7.68 (s, 1H), 7.22 (d, J=5.1 Hz, 1H),7.21 (s, 1H), 5.69-5.60 (m, 1H), 2.04 (s, 3H), 1.89 (s, 3H), 1.47 (d,J=6.6 Hz, 3H).

Example 128N-{1-[5-Chloro-6-methyl-4′-(methylsulfonyl)-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine

Step A:1-[3-Bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethanamine

The desired compound was prepared according to the procedure of Example124, step D, using1-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethanoneas the starting material in 95% yield. LCMS for C₁₅H₂₃BrClN₂O₂ (M+H)⁺:m/z=377.1, 379.1. Found: 377.1, 379.1.

Step B:N-{1-[3-Bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

The desired compound was prepared according to the procedure of Example125, step C, using1-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethanamineas the starting material in 50% yield. LCMS for C₂₅H₃₃BrClN₆O₃ (M+H)⁺:m/z=579.1, 581.1. Found: 579.2, 581.2.

Step C:N-{1-[5-Chloro-6-methyl-4′-(methylsulfonyl)-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine

The desired compound was prepared according to the procedure of Example125, step D, usingN-{1-[3-bromo-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine,[4-(methylsulfonyl)phenyl]boronic acid, and sodium carbonate (instead ofpotassium carbonate) as the starting materials in 27% yield. LCMS forC₂₇H₃₂ClN₆O₄S (M+H)⁺: m/z=571.2. Found: 571.3; ¹H NMR (400 MHz,DMSO-d₆): δ 12.9 (s, 1H), 8.17-8.07 (m, 3H), 8.00 (d, J=7.9 Hz, 2H),7.67 (s, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H), 5.80 (s,1H), 4.15-3.84 (m, 1H), 3.42-3.37 (m, 4H), 3.28 (s, 3H), 2.32-2.25 (m,2H), 2.17-2.12 (m, 2H), 2.08-2.00 (m, 2H), 1.98 (s, 3H), 1.50 (d, J=6.9Hz, 3H).

Experimental procedures for further compounds are summarized in Table 6below.

TABLE 6

Ex. No. Name R₃ Salt Proc.¹ 129 N-{1-[4-chloro-3′,5′- difluoro-6-(2-methoxypyrimidin-5- yl)biphenyl-2-yl]ethyl}- 9H-purin-6-amine

— 124 130 N-{5′-chloro-3″,5″- difluoro-3′-[1-(9H- purin-6-ylamino)ethyl]-1,1′:2′,1″- terphenyl-4-yl} acetamide

— 124 131 N-[1-(4-chloro-3′,5′- difluoro-6-pyridin- 4-ylbiphenyl-2-yl)ethyl]-9H-purin- 6-amine

— 124 132 N-[1-(4-chloro-3′,5′- difluoro-6-pyrimidin- 5-ylbiphenyl-2-yl)ethyl]-9H-purin- 6-amine

— 124 133 N-{1-[4-chloro-6- (2,6-difluoropyridin- 4-yl)-3′-5′-difluorobiphenyl- 2-yl]ethyl}-9H-purin- 6-amine

— 124 134 N-{1-[5′-chloro-3″,5″- difluoro-4- (methylsulfonyl)-1,1′:2′,1″-terphenyl- 3′-yl]ethyl}-9H-purin- 6-amine

— 124 135 N-{1-[6-(2- aminopyrimidin-5-yl)- 4-chloro-3′,5′-difluorobiphenyl-2- yl]ethyl}-9H-purin- 6-amine

— 124

Experimental procedures for further compounds are summarized in Table 7below.

TABLE 7

Ex. No. Name R₃ Salt Proc.¹ 136 N-{1-[5-chloro-2- methoxy-3-(2-methoxypyrimidin- 5-yl)phenyl]ethyl}- 9H-purin-6-amine

— 125 137 N-{5′-chloro-2′- methoxy-3′-[1- (9H-purin-6- ylamino)ethyl]biphenyl-4-yl} acetamide

— 125 138 N-{1-[5-chloro-2- methoxy-3-(1- methyl-1H-pyrazol-5-yl)phenyl]ethyl}- 9H-purin-6-amine

— 125 139 N-[1-(5-chloro-2- methoxy-3-pyridin- 4-ylphenyl)ethyl]-9H-purin-6-amine

— 125 140 N-[1-(5-chloro-2- methoxy-3-pyrimidin- 5-ylphenyl)ethyl]-9H-purin-6-amine

— 125 141 N-{1-[5-chloro-3- (2,6-difluoropyridin- 4-yl)-2-methoxy-phenyl]ethyl}-9H- purin-6-amine

— 125 142 N-{1-[5-chloro-2- methoxy-4′- (methylsulfonyl)biphenyl-3-yl]ethyl}- 9H-purin-6- amine

— 125 143 N-{1-[3-(2- aminopyrimidin- 5-yl)-5-chloro-2- methoxyphenyl]ethyl}-9H-purin- 6-amine

— 125 144 3,5′-dichloro-2′- methoxy-N- methyl-3′-[1- (9H-purin-6-ylamino)ethyl] biphenyl-4- carboxamide

— 125 145 N-{1-[5-chloro-3- (2-fluoropyridin- 4-yl)-2-methoxy-phenyl]ethyl}-9H- purin-6-amine

— 125 146 N-{1-[5-chloro-2- methoxy-3-(5- methoxypyridin-3-yl)phenyl]ethyl}- 9H-purin-6-amine

— 125 147 N-{1-[5-chloro-3- (6-fluoropyridin- 3-yl)-2-methoxy-phenyl]ethyl}-9H- purin-6-amine

— 125 148 N-{1-[5-chloro-2- methoxy-3-(6- methoxypyridin-3-yl)phenyl]ethyl}- 9H-purin-6-amine

— 125

Experimental procedures for compounds below are summarized in Table 8.

TABLE 8

Ex. No. Name R₃ Salt Proc.¹ 149 N-{1-[3-(2- aminopyrimidin-5-yl)-5-chloro- 4-methyl-2-(2- morpholin-4- ylethoxy)phenyl]ethyl}-9H-purin-6- amine

— 128 150 N-{1-[5-chloro-3′- methoxy-6-methyl- 2-(2-morpholin-4-ylethoxy)biphenyl- 3-yl]ethyl}-9H- purin-6-amine

— 128 151 N-{1-[5-chloro-3- (5-chloropyridin- 3-yl)-4-methyl-2-(2-morpholin-4- ylethoxy)phenyl] ethyl}-9H-purin-6- amine

— 128 152 N-{1-[5-chloro-4- methyl-3-(1-methyl- 1H-pyrazol-5-yl)-2-(2-morpholin- 4-ylethoxy)phenyl] ethyl}-9H- purin-6-amine

— 128 153 N-{1-[5-chloro-3′, 4′-dimethoxy-6- methyl-2-(2- morpholin-4-ylethoxy)biphenyl- 3-yl]ethyl}-9H- purin-6-amine

— 128 154 3,3′-dichloro-N,2′- dimethyl-6′-(2- morpholin-4-ylethoxy)-5′-[1- (9H-purin-6- ylamino) ethyl]biphenyl- 4-carboxamide

— 128 155 N-{1-[5-chloro- 4-methyl-3-[5- (morpholin- 4-ylcarbonyl)pyridin-3-yl]-2-(2- morpholin-4- ylethoxy)phenyl] ethyl}-9H-purin-6-amine

— 128 156 N-{1-[5-chloro-4- methyl-3-[5- (methylsulfonyl)pyridin-3-yl]-2- (2-morpholin-4- ylethoxy)phenyl] ethyl}-9H-purin-6-amine

— 128 157 N-{1-[5-chloro-3- (5-methoxypyridin- 3-yl)-4-methyl-2-(2-morpholin-4- ylethoxy)phenyl] ethyl}-9H-purin-6- amine

— 128 158 N-(5-{3-chloro-2- methyl-6-(2- morpholin-4- ylethoxy)-5-[1-(9H-purin-6- ylamino)ethyl] phenyl}pyridin-2- yl)acetamide

— 128 159 3′-chloro-5-fluoro- 2′-methyl-6′-(2- morpholin-4-ylethoxy)-5′-[1- (9H-purin-6- ylamino)ethyl] biphenyl-3- carboxamide

— 128 160 N-{1-[5-chloro-3- (5-fluoro-6- methoxypyridin-3-yl)-4-methyl-2- (2-morhplin-4- ylethoxy)phenyl] ethyl}-9H-purin-6-amine

— 128 161 N-{1-[5-chloro- 3-(2-methoxy- pyrimidin-5-yl)- 4-methyl-2-(2-morpholin-4- ylethoxy)phenyl] ethyl}-9H- purin-6-amine

— 128 162 N-{1-[5-chloro- 3-(5-fluoropyridin- 3-yl)-4-methyl-2-(2-morpholin-4- ylethoxy)phenyl] ethyl}-9H-purin-6- amine

— 128 ¹Synthesized according to the experimental procedure of compoundlisted.

¹H NMR data (Varian Inova 500 spectrometer, a Mercury 400 spectrometer,or a Varian (or Mercury) 300 spectrometer) and LCMS mass spectral data(MS) for the compounds above is provided below in Table 9.

TABLE 9 Ex. MS No. [M + H]⁺ Solvent MHz ¹H NMR Spectra 129 494.1 DMSO-300 δ 8.34 (s, 2 H), 8.26-8.18 (m, 1 H), 8.09 (s, 1 H), 8.05 (s, 1 d₆H), 7.87 (d, J = 1.8 Hz, 1 H), 7.42 (d, J = 2.1 Hz, 1 H), 7.33 (d, J =8.5 Hz, 1 H), 7.17 (dd, J = 9.4, 9.4 Hz, 1 H), 6.82 (d, J = 8.8 Hz, 1H), 5.22-5.07 (m, 1 H), 3.84 (s, 3 H), 1.35 (d, J = 7.0 Hz, 3 H) 130519.0 DMSO- 300 δ 9.89 (s, 1 H), 8.22-8.15 (m, 1 H), 8.09 (s, 1 H), 8.05(s, 1 d₆ H), 7.77 (d, J = 2.1 Hz, 1 H), 7.39 (d, J = 8.5 Hz, 2 H), 7.27(d, J = 7.3 Hz, 1 H), 7.22 (d, J = 2.3 Hz, 1 H), 7.12-7.05 (m, 1 H),6.99 (d, J = 8.8 Hz, 2 H), 6.79 (d, J = 9.7 Hz, 1 H), 5.27-5.08 (m, 1H), 1.99 (s, 3 H), 1.34 (d, J = 7.0 Hz, 3 H) 131 463.0 DMSO- 300 δ 8.41(dd, J = 4.7, 1.5 Hz, 2 H), 8.29-8.20 (m, 1 H), d₆ 8.10 (s, 1 H), 8.06(s, 1 H), 7.87 (d, J = 2.1 Hz, 1 H), 7.34-7.26 (m, 2 H), 7.17-7.10 (m, 3H), 6.88 (d, J = 8.8 Hz, 1 H), 5.25-5.09 (m, 1 H), 1.36 (d, J = 6.7 Hz,3 H) 132 464.0 DMSO- 300 δ 8.99 (s, 1 H), 8.56 (s, 2 H), 8.26-8.18 (m, 1H), 8.09 (s, 1 d₆ H), 8.05 (s, 1 H), 7.91 (d, J = 1.8 Hz, 1 H), 7.48 (d,J = 2.1 Hz, 1 H), 7.35 (d, J = 9.1 Hz, 1 H), 7.15 (dd, J = 9.7, 9.4 Hz,1 H), 6.95 (d, J = 8.8 Hz, 1 H), 5.26-5.06 (m, 1 H), 1.36 (d, J = 6.7Hz, 3 H) 133 499.0 DMSO- 300 δ 8.30-8.23 (m, 1 H), 8.10 (s, 1 H), 8.06(s, 1 H), 7.93 (d, J = 1.8 Hz, d₆ 1 H), 7.82 (s, 1 H), 7.44 (d, J = 2.3Hz, 1 H), 7.36 (d, J = 8.8 Hz, 1 H), 7.22-7.15 (m, 1 H), 6.99 (s, 2 H),6.96 (d, J = 9.1 Hz, 1 H), 5.23-5.09 (m, 1 H), 1.36 (d, J = 7.0 Hz, 3 H)135 412.0 DMSO- 300 δ 8.80 (s, 2 H), 8.24-8.16 (m, 1 H), 8.13 (s, 1 H),8.10 (s, 1 d₆ H), 7.63 (br s, 1 H), 7.39 (d, J = 2.6 Hz, 1 H), 5.88-5.72(m, 1 H), 3.96 (s, 3 H), 3.55 (s, 3 H), 1.51 (d, J = 7.0 Hz, 3 H) 136437.0 DMSO- 300 δ 10.1 (s, 1 H), 8.17-8.09 (m, 3 H), 7.65 (d, J = 8.5Hz, 2 d₆ H), 7.51-7.48 (m, 3 H), 7.18 (d, J = 2.6 Hz, 1 H), 5.89-5.73(m, 1 H), 3.45 (s, 3 H), 2.05 (s, 3 H), 1.50 (d, J = 6.8 Hz, 3 H) 137384.0 DMSO- 300 δ 8.20-8.09 (m, 3 H), 7.65 (br s, 1 H), 7.50 (d, J = 1.8Hz, 1 d₆ H), 7.22 (d, J = 2.9 Hz, 1 H), 6.40 (d, J = 1.8 Hz, 1 H),5.91-5.72 (m, 1 H), 3.67 (s, 3 H), 3.46 (s, 3 H), 1.49 (d, J = 7.0 Hz, 3H) 138 381.0 DMSO- 300 δ 8.64 (dd, J = 4.4, 1.5 Hz, 2 H), 8.25-8.17 (m,1 H), d₆ 8.13 (s, 1 H), 8.10 (s, 1 H), 7.65 (br s, 1 H), 7.59 (dd, J =4.4, 1.5 Hz, 2 H), 7.33 (d, J = 2.6 Hz, 1 H), 5.90-5.72 (m, 1 H), 3.50(s, 3 H), 1.51 (d, J = 7.0 Hz, 3 H) 139 382.0 DMSO- 300 δ 13.0-12.8 (brs, 1 H), 9.21 (s, 1 H), 9.01 (s, 2 H), d₆ 8.28-8.19 (m, 1 H), 8.14 (s, 1H), 8.10 (s, 1 H), 7.68 (br s, 1 H), 7.46 (d, J = 2.6 Hz, 1 H),5.88-5.74 (m, 1 H), 3.53 (s, 3 H), 1.52 (d, J = 7.0 Hz, 3 H) 140 417.0DMSO- 300 δ 8.22-8.16 (m, 1 H), 8.11 (s, 1 H), 8.08 (s, 1 H), 7.71 (d, J= 2.1 Hz, d₆ 1 H), 7.45 (d, J = 2.6 Hz, 1 H), 7.43 (s, 2 H), 5.88-5.75(m, 1 H), 3.59 (s, 3 H), 1.51 (d, J = 7.0 Hz, 3 H) 134 540.0 DMSO- 300 δ12.9 (br s, 1 H), 8.30 (br s, 1 H), 8.13 (s, 1 H), 8.07 (s, 1 d₆ H),7.87 (s, 1 H), 7.75 (d, J = 8.2 Hz, 2 H), 7.38 (d, J = 8.5 Hz, 2 H),7.33 (d, J = 2.1 Hz, 1 H), 7.28 (d, J = 9.1 Hz, 1 H), 7.12 (dd, J = 9.4Hz, 1 H), 6.88 (d, J = 8.5 Hz, 1 H), 5.23-5.09 (m, 1 H), 3.18 (s, 3 H),1.36 (d, J = 6.7 Hz, 3 H) 135 479.0 DMSO- 300 δ 12.9 (br s, 1 H), 8.29(br s, 1 H), 8.12 (s, 1 H), 8.06 (s, 1 d₆ H), 7.92 (s, 2 H), 7.79 (s, 1H), 7.34-7.27 (m, 2 H), 7.16 (dd, J = 9.4, 9.1 Hz, 1 H), 6.93 (d, J =8.8 Hz, 1 H), 6.64 (s, 2 H), 5.19-5.07 (m, 1 H), 1.34 (d, J = 7.0 Hz, 3H) 142 458.0 DMSO- 300 δ 8.28-8.23 (m, 1 H), 8.15 (s, 1 H), 8.12 (s, 1H), 8.00 (d, J = 8.5 Hz, d₆ 2 H), 7.85 (s, J = 8.5 Hz, 2 H), 7.64 (s, 1H), 7.32 (d, J = 2.6 Hz, 1 H), 5.88-5.75 (m, 1 H), 3.47 (s, 3 H), 3.27(s, 3 H), 1.52 (d, J = 7.0 Hz, 3 H) 143 397.0 DMSO- 300 δ 12.9 (br s, 1H), 8.44 (s, 2 H), 8.25-8.09 (m, 3 H), 7.52 (br d₆ s, 1 H), 7.28 (d, J =2.6 Hz, 1 H), 6.85 (s, 2 H), 5.85-5.71 (m, 1 H), 3.57 (s, 3 H), 1.50 (d,J = 6.7 Hz, 3 H) 144 471.0 DMSO- 300 δ 12.9 (s, 1 H), 8.46-8.42 (m, 1H), 8.28-8.22 (m, 1 H), d₆ 8.14-8.09 (m, 2 H), 7.69 (s, 1 H), 7.64-7.57(m, 2 H), 7.49 (d, J = 7.9 Hz, 1 H), 7.28 (d, J = 2.3 Hz, 1 H),5.87-5.73 (m, 1 H), 3.51 (s, 3 H), 2.76 (d, J = 4.7 Hz, 3 H), 1.51 (d, J= 7.0 Hz, 3 H) 145 399.1 DMSO- 300 δ 13.0 (s, 1 H), 8.39-8.20 (m, 2 H),8.20-8.06 (m, 2 H), d₆ 7.70 (s, 1 H), 7.59 (d, J = 5.1 Hz, 1 H), 7.41(s, 2 H), 5.82 (s, 1 H), 3.55 (s, 3 H), 1.52 (d, J = 6.9 Hz, 3 H) 146411.1 DMSO- 300 δ 8.35 (d, J = 1.8 Hz, 1 H), 8.31 (d, J = 2.6 Hz, 1 H),d₆ 8.25-8.20 (m, 1 H), 8.14 (s, 1 H), 8.11 (s, 1 H), 7.62 (s, 1 H), 7.55(d, J = 2.9, 2.1 Hz, 1 H), 7.35 (d, J = 2.9 Hz, 1 H), 5.88-5.74 (m, 1H), 3.87 (s, 3 H), 3.50 (s, 3 H), 1.52 (d, J = 7.0 Hz, 3 H) 147 399.1DMSO- 300 δ 8.42 (d, J = 2.3 Hz, 1 H), 8.27-8.11 (m, 4 H), 7.63 (s, 1 d₆H), 7.35 (d, J = 2.6 Hz, 1 H), 7.29 (dd, J = 8.5, 2.6 Hz, 1 H),5.88-5.74 (m, 1 H), 3.50 (s, 3 H), 1.52 (d, J = 6.7 Hz, 3 H) 148 411.0DMSO- 300 δ 8.34 (d, J = 2.3 Hz, 1 H), 8.25-8.06 (m, 3 H), 7.93 (dd, J =8.6, d₆ 2.4 Hz, 1 H), 7.57 (s, 1 H), 7.28 (d, J = 2.6 Hz, 1 H), 6.91 (d,J = 8.6 Hz, 1 H), 5.82 (s, 1 H), 3.90 (s, 3 H), 3.50 (s, 3 H), 1.51 (d,J = 6.9 Hz, 3 H) 149 510.2 DMSO- 400 δ 12.7 (s, 1 H), 8.22-8.10 (m, 3H), 8.07 (s, 1 H), 7.60 (s, 1 d₆ H), 6.78 (s, 2 H), 5.86-5.70 (m, 1 H),4.11-3.94 (m, 1 H), 3.55-3.37 (m, 5 H), 2.46-2.35 (m, 2 H), 2.32-2.21(m, 2 H), 2.21-2.11 (m, 2 H), 2.08 (s, 3 H), 1.48 (d, J = 6.9 Hz, 3 H)150 523.3 DMSO- 400 δ 12.9 (s, 1 H), 8.21-8.00 (m, 2 H), 7.61 (d, J =3.3 Hz, 1 d₆ H), 7.41-7.30 (m, 1 H), 6.95 (dd, J = 8.0, 2.3 Hz, 1 H),6.89-6.74 (m 2 H), 5.90-5.73 (m, 1 H), 4.05-3.92 (m, 1 H), 3.76 (d, J =4.9 Hz, 4 H), 3.53-3.39 (m, 5 H), 2.41-2.22 (m, 2 H), 2.20-2.12 (m, 2H), 2.11-2.01 (m, 2 H), 1.98 (s, 3 H), 1.49-1.48 (m, 3 H) 151 528.2DMSO- 400 δ 8.68 (s, 1 H), 8.54 (s, 0.5 H), 8.42 (s, 0.5 H), d₆8.18-7.99 (m, 3.5 H), 7.92 (s, 0.5 H), 7.70 (s, 1 H), 5.80 (s, 1 H),4.16-4.07 (m, 1 H), 3.43 (s, 5 H), 2.35-2.25 (m, 2 H), 2.24-2.14 (m, 2H), 2.15-2.05 (m, 2 H), 2.01 (s, 3 H), 1.49 (d, J = 6.8 Hz, 3 H) 152497.3 DMSO- 400 δ 8.25-7.89 (m, 3 H), 7.74 (s, 0.33 H), 7.66 (s, 0.66H), d₆ 7.57-7.48 (m, 1 H), 6.38 (d, J = 1.7 Hz, 0.66 H), 6.31 (d, J =1.7 Hz, 0.33 H), 5.98-5.67 (m, 1 H), 4.28-4.00 (m, 1 H), 3.87-3.70 (m, 1H), 3.65-3.33 (m, 7 H), 2.47-2.12 (m, 6 H), 2.02 (s, 2 H), 1.97 (s, 1H), 1.59-1.39 (m, 3 H) 153 553.3 DMSO- 400 δ 12.9 (s, 1 H), 8.11-8.07(m, 3 H), 7.59 (d, J = 7.3 Hz, 1 d₆ H), 7.01 (d, J = 8.1 Hz, 1 H), 6.89(s, 0.66 H), 6.84-6.71 (m, 1.33 H), 6.05-5.60 (m, 1 H), 3.99-3.95 (m, 1H), 3.79 (s, 3 H), 3.73 (d, J = 6.7 Hz, 3 H), 3.53-3.36 (m, 5 H),2.41-2.23 (m, 2 H), 2.23-2.02 (m, 4 H), 2.00 (s, 3 H), 1.49 (d, J = 4.9Hz, 3 H) 154 584.2 DMSO- 400 δ 12.87 (s, 1 H), 8.39 (dd, J = 4.5, 4.5Hz, 1 H), 8.12 (s, 2 d₆ H), 8.07 (d, J = 5.0 Hz, 1 H), 7.65 (s, 1 H),7.55-7.47 (m, 1.5 H), 7.41-7.32 (m, 1 H), 7.26 (d, J = 7.7 Hz, 0.5 H),5.79 (s, 1 H), 4.02 (s, 1 H), 3.44 (s, 5 H), 2.77 (d, J = 4.6 Hz, 3 H),2.38-2.25 (m, 2 H), 2.27-2.15 (m, 2 H), 2.15-2.05 (m, 2 H), 1.99 (s, 3H), 1.50 (d, J = 6.5 Hz, 3 H) 155 607.3 DMSO- 400 δ 12.9 (s, 1 H),8.66-8.61 (m, 1.5 H), 8.51 (s, 0.5 H), d₆ 8.27-8.20 (m, 1 H), 8.12 (s, 1H), 8.06 (s, 1 H), 7.90 (s, 0.5 H), 7.76 (s, 0.5 H), 7.70 (s, 1 H), 5.79(br s, 1 H), 4.10-4.01 (m, 1 H), 3.68-3.55 (m, 6 H), 3.42-3.33 (m, 7 H),2.32-2.24 (m, 2 H), 2.23-2.15 (m, 2 H), 2.11-2.05 (m, 2 H), 2.02 (s, 1.5H), 1.99 (s, 1.5 H), 1.49 (d, J = 6.1 Hz, 3 H) 156 572.3 DMSO- 400 δ9.01 (s, 1 H), 8.93 (s, 0.5 H), 8.81 (s, 0.5 H), 8.38 (s, 0.5 d₆ H),8.26-8.18 (m, 1.5 H), 8.14 (s, 1 H), 8.07 (s, 1 H), 7.72 (s, 1 H), 5.78(br s, 1 H), 4.14-4.03 (m, 1 H), 3.40-3.36 (m, 5 H), 3.32 (s, 3 H),2.30-2.24 (m, 2 H), 2.20-2.14 (m, 2 H), 2.12-2.05 (m, 2 H), 2.02 (s, 3H), 1.50 (d, J = 6.8 Hz, 3 H) 157 524.3 DMSO- 400 δ 12.9 (br s, 1 H),8.31 (s, 1 H), 8.15-8.06 (m, 2.5 H), d₆ 8.02 (m, 0.5 H), 7.69-7.63 (m, 1H), 7.44 (s, 0.5 H), 7.29 (s, 0.5 H), 5.78 (br s, 1 H), 4.07-3.99 (m, 1H), 3.84 (s, 1.5 H), 3.83 (s, 1.5 H), 3.42-3.38 (m, 5 H), 2.32-2.25 (m,2 H), 2.21-2.13 (m, 2 H), 2.12-2.04 (m, 2 H), 1.99 (s, 3 H), 1.49 (d, J= 6.8 Hz, 3 H) 158 551.3 DMSO- 400 δ 12.9 (br s, 1 H), 10.6-10.6 (m, 1H), 8.22-8.10 (m, 3 H), d₆ 8.07 (s, 1 H), 5.77 (br s, 1 H), 4.05-3.96(m, 1 H), 3.41-3.36 (m, 5 H), 2.38-2.27 (m, 2 H), 2.20-2.13 (m, 2 H),2.11 (s, 3 H), 2.09-2.04 (m, 2 H), 2.01 (s, 3 H), 1.49 (d, J = 6.6 Hz, 3H) 159 554.3 DMSO- 400 δ 12.9 (br s, 1 H), 8.19-8.05 (m, 4 H), 7.72-7.64(m, 2.5 d₆ H), 7.61 (s, 0.5 H), 7.58 (s, 1 H), 7.47 (d, J = 8.4 Hz, 0.5H), 7.32 (d, J = 9.4 Hz, 0.5 H), 5.77 (br s, 1 H), 4.08-4.01 (m, 1 H),3.40-3.35 (m, 5 H), 2.33-2.27 (m, 2 H), 2.19-2.12 (m, 2 H), 2.08-2.02(m, 2 H), 1.98 (s, 3 H), 1.49 (d, J = 5.1 Hz, 3 H) 160 542.3 DMSO- 400 δ12.9 (br s, 1 H), 8.17-8.10 (m, 2 H), 8.07 (s, 1 H), d₆ 7.97-7.94 (m,0.5 H), 7.87-7.80 (m, 1 H), 7.67-7.64 (m, 1.5 H), 5.78 (br s, 1 H),4.08-4.01 (m, 1 H), 3.98 (s, 3 H), 3.42-3.39 (m, 5 H), 2.41-2.30 (m, 2H), 2.24-2.17 (m, 2 H), 2.14-2.07 (m, 2 H), 2.02 (s, 3 H), 1.48 (d, J =6.8 Hz, 3 H) 161 525.3 DMSO- 400 δ 12.9 (br s, 1 H), 8.64-8.54 (m, 2 H),8.20-8.10 (m, 2 H), d₆ 8.07 (s, 1 H), 7.67 (s, 1 H), 5.77 (br s, 1 H),4.09-4.04 (m, 1 H), 3.96 (s, 3 H), 3.43-3.34 (m, 5 H), 2.41-2.29 (m, 2H), 2.25-2.19 (m, 2 H), 2.13-2.09 (m, 2 H), 2.04 (s, 3 H), 1.49 (d, J =7.0 Hz, 3 H) 162 512.3 DMSO- 400 δ 12.9 (br s, 1 H), 8.63 (s, 1 H), 8.44(s, 0.5 H), 8.33 (s, 0.5 d₆ H), 8.19-8.11 (m, 2 H), 8.07 (s, 1 H), 7.91(d, J = 8.8 Hz, 0.5 H), 7.74 (d, J = 10.0 Hz, 0.5 H), 7.69 (s, 1 H),5.77 (br s, 1 H), 4.10-4.01 (m, 1 H), 3.42-3.38 (m, 5 H), 2.32-2.27 (m,2 H), 2.23-2.16 (m, 2 H), 2.13-2.05 (m, 2 H), 2.00 (s, 3 H), 1.49 (d, J= 6.8 Hz, 3 H)

Example 163N-[1-(5-Chloro-2-methoxy-4-methyl-3-pyridazin-4-ylphenyl)ethyl]-9H-purin-6-aminebis(trifluoroacetate)

A mixture ofN-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(0.030 g, 0.062 mmol, from Example 113, step 2 chiral intermediate),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (0.015 g,0.075 mmol, from Milestone Pharmtech), 1 M sodium carbonate solution(0.15 mL, 0.16 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.3mg, 0.0037 mmol) in 1,4-dioxane (0.5 mL) was bubbled with N₂ for 5minutes, then heated at 90° C. overnight. The cooled reaction wastreated directly with 6.0 M hydrogen chloride in water (0.1 mL, 0.6mmol) at room temperature (rt) for ˜30 minutes. The mixture was dilutedwith MeOH, filtered and purified on prep-LCMS (XBridge C18 Column,eluting with a gradient of acetonitrile in water with 0.05%trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desiredproduct as TFA salt. LCMS calculated for C₁₉H₁₉ClN₇O (M+H)⁺: m/z=396.1.found: 396.1.

Example 164N-{1-[5-Chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethyl}-9H-purin-6-aminetrifluoroacetate

Step 1.1-[5-Chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone

4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (2.2 mL, 15 mmol) was added to amixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (2.0 g,6.2 mmol, from Example 60, Step 2), bis(acetonitrile)palladium(II)chloride (32 mg, 0.12 mmol),2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (0.20 g, 0.49mmol) and triethylamine (2.6 mL, 18 mmol) in 1,4-dioxane (3.7 mL) underN₂ and then the mixture was degassed with N₂. The reaction was thenheated at 100° C. for 3 hours. The mixture was cooled to roomtemperature, filtered and purified on silica gel column (eluting with 0to 20% EtOAc in hexanes) to give the desired product (1.3 g, 65%). LCMScalculated for C₁₆H₂₃BClO₄ (M+H)⁺: m/z=325.1. found: 325.1.

Step 2.1-[5-Chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethanone

Into a microwave vial was added1-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone(0.040 g, 0.12 mmol), 4-bromo-1,3-thiazole (0.024 g, 0.15 mmol), 1 Msodium carbonate solution (0.30 mL, 0.31 mmol), 1,4-dioxane (1 mL) andtetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0074 mmol). Themixture was bubbled with N₂ for 5 minutes, and then heated at 95° C.overnight. The cooled reaction was purified on silica gel column(eluting with 0 to 30% EtOAc in hexanes) to give the desired product.LCMS calculated for C₁₃H₁₃ClNO₂S (M+H)⁺: m/z=282.0. found: 282.0.

Step 3.1-[5-Chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethanamine

A mixture of1-[5-chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethanone (6.0mg, 0.021 mmol), ammonium acetate (20 mg, 0.2 mmol) and 1.0 M sodiumcyanoborohydride in THF (0.053 mL, 0.053 mmol) in methanol (0.05mL)/acetonitrile (0.05 mL) was heated at 65° C. overnight. The mixturewas cooled to room temperature, quenched with sat. NaHCO₃ solution,extracted with dichloromethane. The combined organic layers were driedover MgSO₄ and concentrated to give the crude product, which was used inthe next step directly. LCMS calculated for C₁₃H₁₃ClNOS (M−NH₂)⁺:m/z=266.1. found: 266.0.

Step 4.N-{1-[5-Chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethyl}-9H-purin-6-aminetrifluoroacetate

A mixture of1-[5-chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethanamine(5.5 mg, 0.019 mmol), 6-bromo-9H-purine (5.8 mg, 0.029 mmol) andN,N-diisopropylethylamine (DIPEA) (0.010 mL, 0.058 mmol) in ethanol (0.1mL) was heated at 100° C. overnight. The mixture was diluted with MeOHand purified on prep-LCMS (XBridge C18 Column, eluting with a gradientof acetonitrile in water with 0.05% trifluoroacetic acid, at flow rateof 30 mL/min) to afford the desired product as TFA salt. LCMS calculatedfor C₁₈H₁₈ClN₆OS (M+H)⁺: m/z=401.1. found: 401.0.

Example 165N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-aminebis(trifluoroacetate)

Step 1. tert-Butyl3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

Zinc (0.227 g, 3.48 mmol) was suspended with 1,2-dibromoethane (0.0434g, 0.231 mmol) in N,N-dimethylformamide (DMF) (4.1 mL). The mixture washeated at 70° C. for 10 min and then cooled to room temperature.Chlorotrimethylsilane (0.029 mL, 0.23 mmol) was added dropwise andstirring was continued for 1 hour. A solution of tert-butyl3-iodoazetidine-1-carboxylate (0.82 g, 2.9 mmol, from Oakwood) in DMF (3mL) was then added and the mixture was heated at 40° C. for 1 h before amixture of 1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (0.987g, 3.04 mmol, from Example 60, Step 2),tris(dibenzylideneacetone)dipalladium(0) (0.052 g, 0.057 mmol) andtri-(2-furyl)phosphine (0.027 g, 0.12 mmol) in DMF (8 mL) was added. Thereaction mixture was warmed to 70° C. and stirred overnight. The mixturewas then cooled to room temperature and partitioned between EtOAc andsat. NH₄Cl solution. The organic layer was washed with water, dried overMgSO₄, concentrated and purified on silica gel (eluting with 0 to 30%EtOAc in hexanes) to give the desired product (0.57 g, 56%). LCMScalculated for C₁₈H₂₄ClNO₄Na (M+Na)⁺: m/z=376.1. found: 376.1.

Step 2. tert-Butyl3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate

A mixture of tert-butyl3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(0.56 g, 1.6 mmol), ammonium acetate (1.0 g, 20 mmol) and 1.0 M sodiumcyanoborohydride in THF (4.0 mL, 4.0 mmol) in methanol (4mL)/acetonitrile (4 mL) was heated at 65° C. overnight. The mixture wascooled to room temperature, quenched with sat. NaHCO₃ solution,extracted with dichloromethane. The organic extracts were dried overMgSO₄ and concentrated to give the crude product, which was used in thenext step without further purifications. LCMS calculated forC₁₈H₂₇ClN₂O₃Na (M+Na)⁺: m/z=377.2. found: 377.1.

Step 3.N-[1-(3-Azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-aminebis(trifluoroacetate)

A mixture of tert-butyl3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate(0.36 g, 1.0 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.43g, 1.5 mmol, from Example 108, Step 1) and DIPEA (0.53 mL, 3.0 mmol) inethanol (6 mL) was heated at 100° C. overnight. The mixture wasconcentrated and purified on silica gel column (eluting with 0 to 100%EtOAc in hexanes) to give tert-butyl3-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate.LCMS calculated for C₂₈H₃₈ ClN₆O₄ (M+H)⁺: m/z=557.3. found: 557.3. TheBoc intermediate isolated was treated with trifluoroacetic acid (0.8 mL,10 mmol) in methylene chloride (5 mL) at room temperature for 1 hour.The mixture was stripped to dryness to give the desired product as TFAsalt. 4 mg of the salt was purified on prep-LCMS (XBridge C18 Column,eluting with a gradient of acetonitrile in water with 0.05%trifluoroacetic acid, at flow rate of 30 mL/min) to afford the desiredproduct as TFA salt. LCMS calculated for C₁₈H₂₂ClN₆O (M+H)⁺: m/z=373.2.found: 373.1

Example 166N-{1-[3-(1-Acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-aminetrifluoroacetate

Acetic anhydride (2.0 μL, 0.021 mmol) was added to a solution ofN-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-aminebis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and thenthe reaction was stirred at room temperature for 30 minutes. The crudemixture was purified on prep-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile in water with 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to afford the desired product as TFA salt. LCMScalculated for C₂₀H₂₄ClN₆O₂ (M+H)⁺: m/z=415.2. found: 415.1

Example 167 Methyl3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylatetrifluoroacetate

Methyl chloroformate (1.6 pt, 0.021 mmol) was added to a solution ofN-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-aminebis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and thenthe reaction was stirred at room temperature for 30 minutes. The crudemixture was purified on prep-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile in water with 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to afford the desired product as TFA salt. LCMScalculated for C₂₀H₂₄ClN₆O₃ (M+H)⁺: m/z=431.2. found: 431.1. ¹H NMR (300MHz, DMSO-d₆) δ 8.30 (1H, br s), 8.18 (2H, m), 7.46 (1H, s), 5.68 (1H,m), 4.31 (3H, m), 4.14 (1H, m), 4.02 (1H, m), 3.75 (3H, s), 3.55 (3H,s), 2.16 (3H, s), 1.44 (3H, d, J=6.9 Hz) ppm.

Example 1683-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N-methylazetidine-1-carboxamidetrifluoroacetate

Methyl isocyanate (1.3 μL, 0.021 mmol) was added to a solution ofN-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-aminebis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and thenthe reaction was stirred at room temperature for 30 minutes. The crudemixture was purified on prep-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile in water with 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to afford the desired product as TFA salt. LCMScalculated for C₂₀H₂₅ClN₇O₂ (M+H)⁺: m/z=430.2. found: 430.2. ¹H NMR (300MHz, DMSO-d₆) δ 8.32 (1H, br s), 8.18 (2H, m), 7.44 (1H, s), 6.31 (1H,m), 5.68 (1H, m), 4.20 (3H, m), 3.96 (1H, m), 3.82 (1H, m), 3.75 (3H,s), 2.52 (3H, s), 2.15 (3H, s), 1.44 (3H, d, J=6.9 Hz) ppm.

Example 169N-(1-{5-Chloro-2-methoxy-4-methyl-3-[1-(methylsulfonyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-aminetrifluoroacetate

Methanesulfonyl chloride (1.6 μL, 0.021 mmol) was added to a solution ofN-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-aminebis(trifluoroacetate) (8.5 mg, 0.014 mmol, from Example 165) and DIPEA(0.015 mL, 0.085 mmol) in methylene chloride (0.5 mL) at 0° C. and thenthe reaction was stirred at room temperature for 30 minutes. The crudemixture was purified on prep-LCMS (XBridge C18 Column, eluting with agradient of acetonitrile in water with 0.05% trifluoroacetic acid, atflow rate of 30 mL/min) to afford the desired product as TFA salt. LCMScalculated for C₁₉H₂₄ClN₆O₃S (M+H)⁺: m/z=451.1. found: 451.0. ¹H NMR(300 MHz, DMSO-d₆) δ 8.22 (1H, brs), 8.15 (2H, m), 7.48 (1H, s), 5.67(1H, m), 4.21 (3H, m), 4.05 (1H, m), 3.96 (1H, m), 3.76 (3H, s), 2.96(3H, s), 2.10 (3H, s), 1.45 (3H, d, J=6.9 Hz) ppm.

Example 170N-{1-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

Step 1. Benzyl3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

Zinc (1.15 g, 17.6 mmol) was suspended with 1,2-dibromoethane (0.101 mL,1.17 mmol) in DMF (21 mL). The mixture was heated at 70° C. for 10 minand then cooled to room temperature. Chlorotrimethylsilane (0.149 mL,1.17 mmol) was added dropwise and stirring was continued for 1 hour. Asolution of benzyl 3-iodoazetidine-1-carboxylate (4.6 g, 15 mmol, fromPharmablock) in DMF (20 mL) was then added and the mixture was heated at40° C. for 1 h before a mixture of1-(5-chloro-3-iodo-2-methoxy-4-methylphenyl)ethanone (5.0 g, 15 mmol,from Example 60, Step 2), tris(dibenzylideneacetone)dipalladium(0) (0.27g, 0.29 mmol) and tri-(2-furyl)phosphine (0.14 g, 0.59 mmol) in DMF (40mL) was added. The reaction mixture was warmed to 70° C. and stirredovernight. The mixture was then cooled to room temperature andpartitioned between ether and sat. NH₄Cl solution. The organic layer waswashed with water, dried over MgSO₄, concentrated and purified on silicagel (eluting with 0 to 20% EtOAc in hexane) to give the desired product(2.5 g, 44%). LCMS calculated for C₂₁H₂₃ClNO₄ (M+H)⁺: m/z=338.1. found:388.1.

Step 2. Benzyl3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate

Titanium tetraethanolate (2.70 mL, 12.9 mmol) was added to a mixture ofbenzyl3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(2.5 g, 6.4 mmol) in 2.0 M ammonia in ethanol (16.1 mL, 32.2 mmol) at 0°C. The solution was stirred at 60° C. under N₂ overnight. Sodiumtetrahydroborate (0.366 g, 9.67 mmol) was added to the above mixture at0° C. and the solution was stirred at room temperature for another 1hour. The reaction mixture was quenched with 2 M ammonia in water andfiltered. The solid was washed with acetonitrile. The solvent wasremoved and the residue was diluted with dichloromethane, washed withwater and brine, dried over MgSO₄ and concentrated to give the desiredproduct (2.47 g, 98%). LCMS calculated for C₂₁H₂₆ClN₂O₃ (M+H)⁺:m/z=389.2. found: 389.1.

Step 3. Benzyl3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate

Di-tert-butyldicarbonate (2.8 g, 13 mmol) was added to a mixture ofbenzyl3-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]azetidine-1-carboxylate(2.47 g, 6.35 mmol) and DIPEA (3.3 mL, 19 mmol) in THF (32 mL). Afterstirring for 2 h at room temperature, the mixture was quenched with sat.NaHCO₃ solution, extracted with EtOAc. The combined organic layers werewashed with water and brine, dried over MgSO₄, concentrated and purifiedon silica gel (eluting with 0 to 30% EtOAc in hexanes) to give thedesired product (1.8 g, 58%). LCMS calculated for C₂₆H₃₃ClN₂O₅Na(M+Na)⁺: m/z=511.2. found: 511.0. The material was applied on chiralHPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size, elutingwith 20% EtOH in hexanes at 15 mL/min, column loading ˜20 mg/injection)to separate the two enantiomers (Retention times: 7.08 min and 8.46min).

Step 4. tert-Butyl[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate

Benzyl3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(720 mg, 1.5 mmol) (second peak from chiral separation of previous step)and 5% palladium on carbon (100 mg) were combined in methanol (40 mL),to which was added 0.25 M HCl in water (11 mL, 2.8 mmol). The suspensionwas hydrogenated under balloon pressure of H₂ at room temperature for 1hour. The suspension was then filtered, neutralized with sat. NaHCO₃solution, concentrated, and extracted with dichloromethane. The combinedorganic layers were dried over MgSO₄ and concentrated to give thedesired product (0.4 g). LCMS calculated for C₁₈H₂₈ClN₂O₃ (M+H)⁺:m/z=355.2. found: 355.1.

Step 5. tert-Butyl{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate

To a mixture of tert-butyl[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate(20 mg, 0.06 mmol) in acetonitrile (0.2 mL)/methanol (0.2 mL)/THF (0.2mL) was added acetone (48 μL, 0.65 mmol). The mixture was stirred atroom temperature for 30 min before the addition of sodiumtriacetoxyborohydride (36 mg, 0.17 mmol). The mixture was stirred atroom temperature for 4 hours. The mixture was then diluted with waterand extracted with dichloromethane. The organic layers were dried overMgSO₄ and concentrated to give the crude product. LCMS calculated forC₂₁H₃₄ClN₂O₃ (M+H)⁺: m/z=397.2. found: 397.2.

Step 6.N-{1-[5-Chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

tert-Butyl{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate(19 mg, 0.048 mmol) was treated with 4.0 M HCl in dioxane (60 μL, 0.24mmol) in methylene chloride (50 μL) at room temperature for 2 hours. Theresultant mixture was concentrated to dryness to give1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethanaminedihydrochloride. A mixture of the HCl salt,6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (20 mg, 0.072 mmol, fromExample 108, Step 1) and DIPEA (42 μL, 0.24 mmol) in ethanol (0.3 mL)was heated at 100° C. overnight. The mixture was treated with 6.0 M HClin water (80 μL, 0.5 mmol) at room temperature for 10 min and thenpurified on prep-LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.05% trifluoroacetic acid, at flow rate of30 mL/min) to afford the desired product as TFA salt. LCMS calculatedfor C₂₁H₂₈ClN₆O (M+H)⁺: m/z=415.2. found: 415.1.

Example 171N-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

Step 1. Benzyl3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate

Benzyl3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate(0.45 g, 0.92 mmol, from Example 170, Step 3, chiral intermediate) andwas treated with 4.0 M HCl in dioxane (2 mL, 8 mmol) in methylenechloride (6 mL) at room temperature for 2 hours. The reaction mixturewas then stripped to dryness to give benzyl3-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylateas a HCl salt. LCMS calculated for C₂₁H₂₆ClN₂O₃ (M+H)⁺: m/z=389.2.found: 389.1. A mixture of the above HCl salt, 6-bromo-9H-purine (0.20g, 1.0 mmol) and DIPEA (0.80 mL, 4.6 mmol) in ethanol (9 mL) was heatedat 100° C. overnight. The mixture was concentrated and purified onsilica gel (eluting with 0 to 5% MeOH in dichloromethane) to give thedesired product (0.25 g, 55% in 2 steps). LCMS calculated forC₂₆H₂₈ClN₆O₃ (M+H)⁺: m/z=507.2. found: 507.1.

Step 2.N-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

Benzyl3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate(255 mg, 0.503 mmol) and 5% palladium (125 mg) was combined in methanol(15 mL), to which was added 0.25 M HCl in water (5.0 mL, 1.2 mmol). Thesuspension was hydrogenated under balloon pressure of H₂ at roomtemperature overnight. The suspension was filtered and concentrated togiveN-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine.LCMS calculated for C₁₈H₂₂ClN₆O (M+H)⁺: m/z=373.2. found: 373.1. Theazetidine intermediate made above was combined with DIPEA (0.26 mL, 1.5mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followedby the addition of 37% formaldehyde (0.19 mL, 2.5 mmol). The mixture wasstirred at room temperature for 10 min before the addition of sodiumtriacetoxyborohydride (0.32 g, 1.5 mmol). The mixture was stirred atroom temperature overnight, then diluted with MeOH and purified onprep-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrilein water with 0.05% trifluoroacetic acid, at flow rate of 30 mL/min) toafford the desired product as TFA salt. LCMS calculated for C₁₉H₂₄ClN₆O(M+H)⁺: m/z=387.2. found: 387.1.

Example 172N-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

Step 1. 1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone

To 4-chloro-3-fluorophenol (20 g, 100 mmol, from Aldrich) was addedacetyl chloride (14.1 mL, 199 mmol) under N₂ with stirring. Theresulting mixture turned into a clear solution at room temperature andwas heated at 60° C. for 2 hours. To the resultant mixture was addedaluminum trichloride (25.0 g, 187 mmol) in portions and the mixture washeated at 180° C. for 30 minutes. The solids slowly dissolved at hightemp. The reaction mixture was then cooled to room temperature while theflask was swirled carefully in order for the solid to form a thin layerinside the flask and then slowly quenched with 1.0 N HCl (300 mL) whilecooling in an ice-bath and stirred overnight. The yellow precipitate waswashed well with water and dried under vacuum to give the desiredproduct as a yellow solid (23.8 g), which was directly used in the nextstep without further purification.

Step 2. 1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone

A solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (23.8 g, 126mmol) in acetic acid (100 mL) was treated with N-iodosuccinimide (34.1g, 151 mmol) and stirred at 70° C. for 2 hours. The reaction mixture wasconcentrated, diluted with EtOAc and quenched with sat. NaHCO₃ solution.The organic layer was separated, washed with water, dried over MgSO₄ andconcentrated under reduced pressure to give the desired product to beused in the next step without further purification.

Step 3. 1-(5-Chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone

1-(5-Chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone (13 g, 41 mmol) wasdissolved in DMF (41.3 mL). Methyl iodide (3.9 mL, 62 mmol) was addedfollowed by potassium carbonate (11 g, 83 mmol). The reaction was heatedat 60° C. for 1 hour. The mixture was cooled to room temperature,diluted with ether, washed with water, dried over MgSO₄, concentrated.The residue was purified on silica gel (eluting with 0 to 10% EtOAc inhexanes) to give the desired product (10 g, 70%). LCMS calculated forC₉H₈ClFIO₂ (M+H)⁺: m/z=328.9. found: 328.9.

Step 4. tert-Butyl3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate

Zinc (0.682 g, 10.4 mmol) was suspended with 1,2-dibromoethane (0.060mL, 0.69 mmol) in DMF (12 mL). The mixture was heated at 70° C. for 10min and then cooled to room temperature. Chlorotrimethylsilane (0.088mL, 0.69 mmol) was added dropwise and stirring was continued for 1 hour.A solution of tert-butyl 3-iodoazetidine-1-carboxylate (2.5 g, 8.7 mmol,from Oakwood) in DMF (10 mL) was then added and the mixture was heatedat 40° C. for 1 h before a mixture of1-(5-chloro-4-fluoro-3-iodo-2-methoxyphenyl)ethanone (3.0 g, 9.1 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.16 g, 0.17 mmol) andtri-(2-furyl)phosphine (0.081 g, 0.35 mmol) in DMF (20 mL) was added.The reaction mixture was warmed to 70° C. and stirred overnight. Themixture was then cooled to room temperature and partitioned betweenether and sat. NH₄Cl solution. The organic layer was washed with water,dried over MgSO₄, concentrated and purified on silica gel (eluting with0 to 25% EtOAc in hexanes) to give the desired product (0.8 g). LCMScalculated for C₁₇H₂₁ClFNO₄Na (M+Na)⁺: m/z=380.1. found: 380.1.

Step 5. tert-Butyl3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate

To a solution of tert-butyl3-(3-acetyl-5-chloro-6-fluoro-2-methoxyphenyl)azetidine-1-carboxylate(0.17 g, 0.48 mmol) in methanol (3 mL) cooled at 0° C. was added sodiumtetrahydroborate (0.022 g, 0.57 mmol). The mixture was stirred at roomtemperature for 1 hour, then diluted with water and extracted withEtOAc. The combined organic layers were dried over MgSO₄ andconcentrated to give the desired product (0.19 g). LCMS calculated forC₁₇H₂₃ClFNO₄Na (M+Na)⁺: m/z=382.1. found: 382.0.

Step 6. tert-Butyl3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate

Cyanuric chloride (140 mg, 0.78 mmol) was added to DMF (0.059 mL, 0.77mmol) at room temperature. After the formation of a white solid (10min), methylene chloride (4 mL) was added, followed by tert-butyl3-[3-chloro-2-fluoro-5-(1-hydroxyethyl)-6-methoxyphenyl]azetidine-1-carboxylate(197 mg, 0.547 mmol). After the addition, the mixture was stirred atroom temperature overnight. Water was added, and the resulting mixturewas then diluted with dichloromethane. The organic phase was separated,washed with sat. NaHCO₃ solution, water and brine, dried over MgSO₄,concentrated and purified on silica gel (eluting with 0 to 30% EtOAc inhexanes) to give the desired product (110 mg, 53%).

Step 7. tert-Butyl3-[3-(1-azidoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate

A mixture of tert-butyl3-[3-chloro-5-(1-chloroethyl)-2-fluoro-6-methoxyphenyl]azetidine-1-carboxylate(0.070 g, 0.18 mmol) and sodium azide (0.036 g, 0.56 mmol) in DMF (0.66mL) was stirred at room temperature overnight. After diluting withether, the mixture was washed with water, dried over MgSO₄ andconcentrated to give the crude azide which was used in the next stepwithout further purification. LCMS calculated for C₁₇H₂₂ClFN₄O₃Na(M+Na)⁺: m/z=407.1. found: 407.0.

Step 8. tert-Butyl3-[3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate

To a stirred solution of tert-butyl3-[3-(1-azidoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate(0.084 g, 0.22 mmol) in THF (1 mL)/water (0.2 mL) was added 1.0 Mtrimethylphosphine in THF (0.33 mL, 0.33 mmol) at room temperature andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was diluted with water and extracted with EtOAc. The combinedorganic layers were dried over MgSO₄ and concentrated to give thedesired product to be used in the next step without furtherpurification.

Step 9.N-{1-[5-Chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

A mixture of tert-butyl3-[3-(1-aminoethyl)-5-chloro-6-fluoro-2-methoxyphenyl]azetidine-1-carboxylate(22.5 mg, 0.0627 mmol), 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(24 mg, 0.085 mmol, from Example 108, Step 1) and DIPEA (33 μL, 0.19mmol) in ethanol (1.0 mL) was heated at 100° C. overnight. The mixturewas diluted with sat. NaHCO₃ solution, extracted with dichloromethane.The combined organic layers were dried over MgSO₄ and concentrated togive tert-butyl3-[3-chloro-2-fluoro-6-methoxy-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]azetidine-1-carboxylate(34 mg). LCMS calculated for C₂₇H₃₅ClFN₆O₄ (M+H)⁺: m/z=561.2. found:561.2. The coupling product made above was treated with 4.0 M HCl indioxane (0.5 mL, 2 mmol) in methylene chloride (0.2 mL) at roomtemperature for 1 hour. The reaction mixture was then evaporated todryness to giveN-[1-(3-azetidin-3-yl-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9H-purin-6-aminedihydrochloride. The resultant HCl salt was dissolved in methanol (0.2mL)/acetonitrile (0.2 mL)/THF (0.2 mL) and treated with DIPEA (0.1 mL,0.6 mmol) until the solid dissolved. Acetone (0.05 mL, 0.6 mmol) wasadded and the resulting mixture was stirred at room temperature for 30min before the addition of sodium triacetoxyborohydride (0.066 g, 0.31mmol). The reaction mixture was stirred at room temperature for 4 h andthen purified on prep-LCMS (XBridge C18 Column, eluting with a gradientof acetonitrile in water with 0.05% trifluoroacetic acid, at flow rateof 30 mL/min) to afford the desired product as TFA salt. LCMS calculatedfor C₂₃H₂₅ClFN₆O (M+11)⁺: m/z=419.2. found: 419.1. ¹H NMR (300 MHz,DMSO-d₆) δ 9.96 (1H, m), 8.41 (1H, m), 8.23 (1H, s), 8.20 (1H, s), 7.53(1H, s), 5.69 (1H, m), 4.52 (2H, m), 4.26 (1H, m), 4.12 (2H, m), 3.77(3H, s), 2.08 (3H, m), 1.46 (3H, d, J=6.9 Hz), 1.11 (6H, m) ppm.

Example 173N-{1-[5-chloro-2-ethoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine

Step 1. 1-(5-Chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone

1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol,from Example 60, Step 1) was dissolved in DMF (61 mL). Iodoethane (7.3mL, 91 mmol) was added followed by potassium carbonate (17.0 g, 120mmol). The reaction was heated at 60° C. for 1 hour. The mixture wascooled to room temperature, diluted with ether, washed with water, driedover MgSO₄, concentrated. The resulting residue was purified on silicagel (eluting with 0 to 10% EtOAc in hexanes) to give the desired product(18.9 g, 91.7%). LCMS calculated for C₁₁H₁₃ClIO₂ (M+H)⁺: m/z=339.0.found: 339.0.

Step 2. Benzyl3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate

Zinc (0.967 g, 14.8 mmol) was suspended with 1,2-dibromoethane (0.085mL, 0.98 mmol) in DMF (17 mL). The mixture was heated at 70° C. for 10min and then cooled to room temperature. Chlorotrimethylsilane (0.13 mL,0.98 mmol) was added dropwise and stirring was continued for 1 hour. Asolution of benzyl 3-iodoazetidine-1-carboxylate (3.9 g, 12 mmol, fromPharmablock) in DMF (10 mL) was then added and the mixture was heated at40° C. for 1 h before a mixture of1-(5-chloro-2-ethoxy-3-iodo-4-methylphenyl)ethanone (4.4 g, 13 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.22 g, 0.24 mmol) andtri-(2-furyl)phosphine (0.12 g, 0.50 mmol) in DMF (30 mL) was added. Thereaction mixture was warmed to 70° C. and stirred overnight. The mixturewas then cooled to room temperature and partitioned between ether andsat. NH₄Cl solution. The organic layer was washed with water, dried overMgSO₄, concentrated and purified on silica gel (eluting with 0 to 20%EtOAc in hexanes) to give the desired product (3.87 g, 78%). LCMScalculated for C₂₂H₂₅ClNO₄ (M+H)⁺: m/z=402.1. found: 402.1.

Step 3. Benzyl3-[3-O-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylate

Titanium tetraethanolate (3.3 mL, 16 mmol) was added to a mixture ofbenzyl3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate(3.2 g, 8.0 mmol) in 2.0 M ammonia in ethanol (19.9 mL, 39.8 mmol) at 0°C. The solution was stirred at 60° C. under N₂ overnight. Sodiumtetrahydroborate (0.452 g, 11.9 mmol) was added to the resultant mixtureat 0° C. and the reaction mixture was stirred at room temperature foranother 1 hour. The mixture was then quenched with 2 M ammonia in waterand filtered. The solid was washed with acetonitrile. The solvent wasremoved and the residue was diluted with dichloromethane, washed withwater and brine, dried over MgSO₄ and concentrated to give the desiredproduct (2.99 g, 93%). LCMS calculated for C₂₂H₂₈ClN₂O₃ (M+H)⁺:m/z=403.2. found: 403.2.

Step 4. Benzyl3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate

Di-tert-butyldicarbonate (3.2 g, 15 mmol) was added to a mixture ofbenzyl3-[3-(1-aminoethyl)-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylate(2.99 g, 7.42 mmol) and DIPEA (3.9 mL, 22 mmol) in THF (37 mL). Afterstirring overnight at room temperature, the mixture was quenched withsat. NaHCO₃ solution, extracted with EtOAc. The combined organic layerswere washed with water and brine, dried over MgSO₄, concentrated andpurified on silica gel (eluting with 0 to 25% EtOAc in hexane) to givethe desired product (2.1 g, 56%). LCMS calculated for C₂₇H₃₅ClN₂O₅Na(M+Na)⁺: m/z=525.2. found: 525.2. The material was applied on chiralHPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size, elutingwith 20% EtOH in hexanes at 15 ml/min, column loading ˜20 mg/injection)to separate the two enantiomers (Retention times: 7.08 min and 8.46min).

Step 5. Benzyl3-{3-chloro-6-ethoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate

Benzyl3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate(65 mg, 0.13 mmol, second peak from chiral separation in previous step)was treated with 4.0 M HCl in dioxane (0.4 mL, 2 mmol) in methylenechloride (0.4 mL, 6 mmol) at room temperature for 2 hours. The reactionmixture was evaporated to dryness to give benzyl3-[3-[1-aminoethyl]-5-chloro-2-ethoxy-6-methylphenyl]azetidine-1-carboxylatehydrochloride. LCMS calculated for C₂₂H₂₈ClN₂O₃ (M+H)⁺: m/z=4012. found:403.1. A mixture of the above HCl salt, 6-bromo-9H-purine (31 mg, 0.16mmol) and DIPEA (0.11 mL, 0.65 mmol) in ethanol (1 mL) was heated at100° C. overnight. The mixture was diluted with sat. NaHCO₃ solution,extracted with dichloromethane. The combined organic layers were driedover MgSO₄ and concentrated to give the desired product (83 mg). LCMScalculated for C₂₇H₃₀ClN₆O₃ (M+H)⁺: m/z=521.2. found: 521.1.

Step 6.N-{1-[5-chloro-2-ethoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine

Benzyl3-{3-chloro-6-ethoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate(83 mg, 0.16 mmol) and 5% palladium (74 mg) was combined in methanol (5mL), to which was added 0.25 M HCl in water (1.6 mL, 0.40 mmol). Thesuspension was hydrogenated under balloon pressure of H₂ at roomtemperature overnight. The suspension was filtered and concentrated togiveN-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-9H-purin-6-amine.LCMS calculated for C₁₉H₂₄ClN₆O (M+H)⁺: m/z=387.2. found: 387.1. Theazetidine made above was combined with DIPEA (0.1 mL, 0.6 mmol) inmethanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by theaddition of 37% formaldehyde (0.1 mL, 2 mmol). The mixture was stirredat room temperature for 10 min before the addition of sodiumtriacetoxyborohydride (0.17 g, 0.80 mmol). The reaction mixture wasstirred at room temperature overnight, then diluted with MeOH andpurified on RP-HPLC (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30mL/min) to give the desired product. LCMS calculated for C₂₀H₂₆ClN₆O(M+H)⁺: m/z=401.2. found: 401.1.

Example 174N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-9H-purin-6-aminetris(trifluoroacetate)

Step 1. tert-Butyl4-{4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate

Into a microwave vial was addedN-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(0.032 g, 0.066 mmol, from Example 113, Step 2, chiral intermediate),tert-butyl4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate(0.030 g, 0.080 mmol, from Combi-Blocks), sodium carbonate (0.014 g,0.13 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) andtetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol). Themixture was degassed with N₂ for 5 minutes, and then heated at 120° C.overnight. The mixture was diluted with EtOAc, washed with sat. NaHCO₃,water, brine, dried over Na₂SO₄, filtered and concentrated to give thecrude product (0.040 g) which was used in the next step directly. LCMScalculated for C₃₃H₄₄ClN₈O₄ (M+H)⁺: m/z=651.3. found: 651.2.

Step 2.N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-9H-purin-6-aminetris(trifluoroacetate)

tert-Butyl4-{4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-1H-pyrazol-1-yl}piperidine-1-carboxylate(0.040 g) was dissolved in CH₂Cl₂ (0.4 mL) and then TFA (0.4 mL) wasadded. The mixture was stirred at room temperature for 1 hour. Afterevaporated to dryness, the residue was purified on RP-HPLC (XBridge C18Column, eluting with a gradient of acetonitrile in water with 0.05%trifluoroacetic acid, at flow rate of 30 mL/min) to give the desiredproduct. LCMS calculated for C₂₃H₂₈ClN₈O (M+H)⁺: m/z=467.2. found:467.2.

Example 1754-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,1-dimethyl-1H-pyrrole-2-carboxamide

Step 1. 2-Benzyl 1-tert-butyl 4-iodo-1H-pyrrole-1,2-dicarboxylate

A mixture of 2,2,2-trichloro-1-(4-iodo-1H-pyrrol-2-yl)ethanone (15.0 g,44.3 mmol, from Ryan Scientific), benzyl alcohol (9.2 mL, 89 mmol), andtriethylamine (8.0 mL, 58 mmol) was heated at 60° C. with stirringovernight. After cooling to room temperature, di-tert-butyldicarbonate(10.6 g, 48.8 mmol), 4-dimethylaminopyridine (542 mg, 4.43 mmol) andmethylene chloride (75.0 mL) was added. The mixture was stirred at roomtemperature for 3 hours. The reaction was then diluted with EtOAc andwashed with water, aqueous citric acid, brine, dried and concentrated.The product was isolated by chromatography eluting with 0 to 10% EtOAcin hexanes. LCMS calculated for C₁₇H₁₈INO₄Na (M+Na)⁺: m/z=450.0. found:450.0.

Step 2. 2-Benzyl 1-tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate

At −78° C. to a solution of 2-benzyl 1-tert-butyl4-iodo-1H-pyrrole-1,2-dicarboxylate (10.0 g, 23.4 mmol), and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.6 mL, 47 mmol)in THF (120 mL) was added dropwise a solution of 2.5 M n-butyllithium inhexane (11.2 mL, 28.1 mmol) with stirring. After completion of additionthe mixture was stirred at this temperature for 35 min and then 2.5 Mn-butyllithium in hexane (1.87 mL, 4.68 mmol) was added and stirred foranother 30 minutes. The reaction was quenched with sat. NH₄Cl solutionand then diluted with EtOAc. The organic layer was separated, washedwith water twice, washed with brine, dried over Na₂SO₄, and concentratedunder reduced pressure. The product was isolated by chromatographyeluting with 0 to 10% EtOAc in hexanes. LCMS calculated for C₁₉H₂₃BNO₆(M−[^(t)Bu+1]+1)⁺: m/z=372.2. found: 372.2.

Step 3. Benzyl1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate

2-Benzyl 1-tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate(0.5 g) was dissolved in CH₂Cl₂ (1 mL) and then 4 N HCl in dioxane (1mL) was added. The reaction was stirred at room temperature for 1 hour.The solvent was removed under vacuum. The residue was redissolved in DMF(4 mL). To the resulting solution was added NaH (60% dispersion inmineral oil, 0.08 g, 2.0 mmol) at 0° C. The reaction mixture was stirredat 0° C. for 10 minutes. Methyl iodide (0.11 mL, 2.0 mmol) was added andthe reaction was stirred at room temperature for 3 hours. The reactionwas quenched with sat. NH₄Cl solution and then diluted with EtOAc. Afterseparation of layers, the organic phase was washed with water (twice)and brine; dried over Na₂SO₄. The solvent was removed to provide thedesired crude product which was used in the next step without furtherpurification. LCMS calculated for C₁₉H₂₅BNO₄ (M+H)⁺: m/z=342.2. found:342.2.

Step 4. Benzyl4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-1-methyl-1H-pyrrole-2-carboxylate

A mixture ofN-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(0.032 g, 0.066 mmol, from Example 113, Step 2, Chiral intermediate),benzyl1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate(0.027 g, 0.080 mmol), sodium carbonate (0.16 mL, 0.17 mmol),1,4-dioxane (0.6 mL)/water (0.2 mL) andtetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol) wasdegassed with N₂ for 5 minutes, then heated at 95° C. overnight. Themixture was diluted with EtOAc, washed with sat. NaHCO₃, water, brine,and dried over Na₂SO₄ and concentrated. The crude product (20 mg, 50%)was purified by chromatography eluting with 0 to 40% EtOAc in CH₂Cl₂.LCMS calculated for C₃₃H₃₆ClN₆O₄ (M+H)⁺: m/z=615.2. found: 615.2.

Step 5.4-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methyl-1H-pyrrole-2-carboxylicacid

Pd/C (5%, 20 mg) was added to a solution of benzyl4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-1-methyl-1H-pyrrole-2-carboxylate(20 mg) in methanol (2.0 mL) and the reaction was stirred at roomtemperature under balloon pressure of H₂ for 4 hours. The reactionmixture was filtered and to the filtrate was added conc. HCl (30 μL).The mixture was stirred for 0.5 h to remove the THP group. The solventwas removed to yield the crude product which was used in the next stepwithout further purification. LCMS calculated for C₂₁H₂₂ClN₆O₃ (M+H)⁺:m/z=441.1. found: 441.2.

Step 6.4-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,1-dimethyl-1H-pyrrole-2-carboxamide

2.0 M Methylamine in THF (0.2 mL, 0.4 mmol) was added to a solution of4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methyl-1H-pyrrole-2-carboxylicacid (10.0 mg, 0.02 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(24 mg, 0.054 mmol) in DMF (0.8 mL) at room temperature followed byaddition of triethylamine (33 μL, 0.24 mmol). The reaction was stirredfor 2 hours. The mixture was purified on RP-HPLC (XBridge C18 Column,eluting with a gradient of acetonitrile in water with 0.2% ammoniumhydroxide, at flow rate of 30 mL/min) to give the desired product. LCMScalculated for C₂₂H₂₅ClN₇O₂ (M+H)⁺: m/z=454.2. found: 454.2.

Example 176N-{1-[5-Chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-9H-purin-6-amine

Step 1. Benzyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-carbamate

Benzyl chloroformate (0.41 mL, 2.8 mmol) was added to a mixture of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanamine hydrochloride(0.50 g, 1.6 mmol, made from Example 113, step 1, chiral intermediate),and sodium carbonate (670 mg, 6.3 mmol) in methylene chloride (5mL)/water (1 mL) at 0° C. The reaction was stirred at room temperaturefor 4 hours. The mixture was diluted with EtOAc, washed with water,brine, dried over Na₂SO₄, filtered and concentrated. The resultantresidue was purified by chromatography eluting with 0 to 20% EtOAc inhexanes to provide the desired product (0.5 g, 76%). LCMS calculated forC₁₈H₁₉BrClNO₃Na (M+Na)⁺: m/z=434.0. found: 434.1.

Step 2. tert-Butyl4-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5-chloro-2-methoxy-6-methylphenyl]-3,6-dihydropyridine-1(2H)-carboxylate

A mixture of benzyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (0.48 g,1.2 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(0.40 g, 1.3 mmol, from Aldrich), sodium carbonate (250 mg, 2.3 mmol)and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (110 mg, 0.14 mmol) in acetonitrile (4.0mL)/water (1 mL) was placed under vacuum and then refilled with N₂. Thereaction was stirred at 95° C. for 3 hours. The mixture was diluted withEtOAc, washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄,filtered and concentrated. The resultant residue was purified bychromatography eluting with 0 to 20% EtOAc in hexanes to provide thedesired product (0.55 g, 90%). LCMS calculated for C₂₈H₃₅ClN₂O₅Na(M+Na)⁺: m/z=537.2. found: 537.3.

Step 3. tert-Butyl4-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-piperidine-1-carboxylate

Platinum on carbon (10 wt. % loading (dry basis), matrix activatedcarbon, 200 mg) was added to a solution of tert-butyl4-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5-chloro-2-methoxy-6-methylphenyl]-3,6-dihydropyridine-1(2H)-carboxylate(200 mg, 0.388 mmol) in ethanol (30 mL)/0.25 M HCl in water (3.9 mL,0.97 mmol) and then the reaction was stirred at room temperature under30 psi of hydrogen atmosphere for 3 d. The mixture was adjusted to basicpH with ammonia and then the solvent was removed. The residue wasdiluted with methylene chloride, washed with sat. NaHCO₃, water, brine,dried over Na₂SO₄, filtered and concentrated to give the crude desiredproduct (0.15 g) which was used in the next step without furtherpurification. LCMS calculated for C₂₀H₃₂ClN₂O₃ (M+H)⁺: m/z=383.2. found:383.3.

Step 4. 6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

To a solution of 6-chloropurine (2.70 g, 17.5 mmol) andp-toluenesulfonic acid monohydrate (0.14 g, 0.71 mmol) in methylenechloride (30 mL) was added dihydropyran (2.39 mL, 26.2 mmol). Thesuspension was stirred for 3 h. The reaction mixture was washed with2.5% Na₂CO₃ solution (100 mL×²), and brine (50 mL). The organic layerwas dried over sodium sulfate and concentrated. The oil was treated withhexanes (100 mL) and stirred. The hexanes layer was decanted. The oilsolidified upon standing to give the desired product (4.17 g, 98%).

Step 5. tert-Butyl4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]piperidine-1-carboxylate

A mixture of tert-butyl4-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}piperidine-1-carboxylate(150 mg, 0.392 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(122 mg, 0.509 mmol), and sodium bicarbonate (35 mg, 0.41 mmol) in1-butanol (4.7 mL) was degassed with N₂ for ˜5 minutes. The mixture washeated at 110° C. for 3 h under nitrogen. The solvent was removed underreduced pressure and the resulting residue was diluted with EtOAc,washed with sat. NaHCO₃, water, brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by chromatography eluting with 0to 80% EtOAc in CH₂Cl₂ to provide the desired product (0.25 g). LCMScalculated for C₃₀H₄₂ClN₆O₄ (M+H)⁺: m/z=585.3. found: =585.3.

Step 6.N-[1-(5-Chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-9H-purin-6-amine

4.0 M HCl in dioxane (2.0 mL, 8 mmol) was added to a solution oftert-butyl4-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]piperidine-1-carboxylate(250 mg, 0.43 mmol) in methylene chloride (1.0 mL, 16 mmol) and thereaction was stirred at room temperature for 1 hour. The solvent wasremoved to provide the desired product as HCl salt which was used in thenext step without further purification. LCMS calculated for C₂₀H₂₆ClN₆O(M+H)⁺: m/z=401.2. found: =401.2.

Step 7.N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-9H-purin-6-amine

12.0 M Formaldehyde in water (0.4 mL, 5 mmol) was added to a mixture ofN-[1-(5-chloro-2-methoxy-4-methyl-3-piperidin-4-ylphenyl)ethyl]-9H-purin-6-amine(200 mg, 0.5 mmol) and DIPEA (0.35 mL, 2.0 mmol) in methylene chloride(5 mL) at 0° C. The reaction was stirred for 10 minutes, and after thistime sodium triacetoxyborohydride (160 mg, 0.75 mmol) was added. Thereaction was stirred at 0° C. for 1 hour. The mixture was purified onRP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile inwater with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to givethe desired product. LCMS calculated for C₂₁H₂₈ClN₆O (M+H)⁺: m/z=415.2.found: 415.3. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.67 (1H, br s), 8.72 (1H, brs), 8.35 (2H, s), 7.51 (1H, s), 5.75 (1H, m), 3.88 (3H, s), 3.49 (2H,m), 3.34 (1H, m), 3.12 (2H, m), 2.81 (1.5H, s), 2.80 (1.5H, s),2.44-2.31 (2H, m), 2.36 (3H, s), 1.79 (2H, m), 1.49 (3H, d, J=6.5 Hz)ppm.

Example 1776-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamidebis(2,2,2-trifluoroacetate)

Step 1. tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate

The tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (1.5 g,4.0 mmol, from Example 113, Step 1 Peak 2), was combined with potassiumacetate (1.2 g, 12 mmol) and4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (2.0 g,7.9 mmol) in dimethyl sulfoxide (15 mL, 210 mmol) at room temperature.The reaction was degassed with nitrogen and the[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (0.3 g, 0.4 mmol) was added. The reactionvessel was sealed and heated in an oil bath to 95° C. After heating for20 h the starting material was consumed. The reaction was allowed tocool and then diluted with EtOAc and washed with water, brine, driedover magnesium sulfate and concentrated to give the crude product as adark colored oil. The oil was purified by chromatography on silica geleluting with a hexane:EtOAc gradient to give tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamateas a semisolid (1.1 g, 65%). LCMS calculated for C₁₆H₂₄BClO₃ (M+H)⁺:m/z=310.6. found: 310.0.

Step 2. methyl6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylate

The tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate(0.3 g, 0.7 mmol), methyl 6-bromopyridine-2-carboxylate (0.38 g, 1.8mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complex with dichloromethane (1:1) (0.0575 g, 0.0705 mmol), palladiumacetate (0.008 g, 0.04 mmol), cuprous monochloride (0.070 g, 0.70 mmol),and cesium carbonate (0.46 g, 1.4 mmol) were combined in DMF (18 mL).The mixture was degassed with nitrogen gas for 5 min and heated to 100°C. overnight in a sealed tube. The reaction was allowed to cool, dilutedwith

EtOAc and washed with water, brine, dried over magnesium sulfate andconcentrated to give crude product as a dark oil. The product waspurified by chromatography on silica gel eluting with hexane:EtOAcgradient to give methyl6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylateas a viscous oil (0.15 g, 50%). LCMS calculated for C₂₂H₂₈ClN₂O₅(M+H)⁺:m/z=435.1. found: 435.1.

Step 3.6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylicacid

The methyl6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylate(0.075 g, 0.17 mmol) was dissolved in methanol (5.0 mL) and the lithiumhydroxide-monohydrate (0.022 g, 0.52 mmol) dissolved in water (0.5 mL)was added. The reaction was stirred at room temperature and monitored byLC/MS. After stirring for 18 h the reaction was complete. Acetic acidwas added to adjust the pH 5 and the reaction was concentrated to give asemisolid residue. The crude was diluted with acetonitrile andconcentrated 3× to remove residual water and finally give6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylicacid as a crude solid residue. LCMS calculated for C₁₇H₁₈ClN₂O₅(M+H)⁺:m/z=365.1. found: 365.0.

Step 4. tert-butyl[1-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-2-yl}-2-methoxy-4-methylphenyl)ethyl]carbamate

The6-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)pyridine-2-carboxylicacid (0.07 g, 0.2 mmol) was combined with DMF (3.0 mL) and DIPEA (0.14mL, 0.83 mmol) at room temperature and theN,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (0.13 g, 0.33 mmol) was added. The reaction stirredfor 10 min and dimethylamine hydrochloride (0.041 g, 0.50 mmol) wasadded. The reaction was stirred at room temperature for 3 h and wascomplete by LC/MS. The reaction mixture was diluted with EtOAc andwashed with water, saturated ammonium chloride, brine, dried overmagnesium sulfate and concentrated to give the desired product as an oil(0.06 g, 83%). LCMS calculated for C₂₃H₃₁ClN₃O₄ (M+H)⁺: m/z=448.2.found: 448.1.

Step 5.6-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamidedihydrochloride

The tert-butyl[1-(5-chloro-3-{6-[(dimethylamino)carbonyl]pyridin-2-yl}-2-methoxy-4-methylphenyl)ethyl]carbamate(0.06 gm, 0.13 mmol) was dissolved in 4 M HCl in dioxane (3 mL) and wasstirred for 1 hour. The reaction was complete and the mixture wasconcentrated in vacuo to give the crude product as an oil. LCMScalculated for C₁₈H₂₃ClN₃O₂(M+H)⁺: m/z=348.1. found: 348.1.

Step 6.6-[3-chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-N,N-dimethylpyridine-2-carboxamide

The6-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-N,N-dimethylpyridine-2-carboxamide(0.025 g, 0.072 mmol) was combined with6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.022 g, 0.14 mmol,from Example 176, Step 4) in 2-methoxyethanol (1.0 mL, 13 mmol) andDIPEA (0.037 g, 0.29 mmol) in a sealed tube. The reaction was heated to105° C. in an oil bath for 18 hours. Without workup, the reaction wascarried into the next step.

Step 7.6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamidebis(2,2,2-trifluoroacetate)

6-[3-Chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-N,N-dimethylpyridine-2-carboxamide(0.04 gm, 0.072 mmol, from Example 177, Step 6) was dissolved in asolution of 4 M HCl in dioxane (2 mL) and was stirred for 1 hour. Thereaction mixture was purified without workup by prep HPLC on a C-18column eluting a water:acetonitrile gradient buffered with TFA (pH 2) togive the desired compound as a white amorphous solid (0.015 g, 45%).LCMS calculated for C₂₃H₂₅ClN₇O₂(M+H)⁺: m/z=466.1. found: 466.0. ¹H NMR(300 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.29 (m, 2H), 8.03 (t, J=7.8 Hz, 1H),7.64 (s, 1H), 7.57 (d, J=7.7 Hz, 1H), 7.49 (d, J=7.7 Hz, 1H), 5.72 (m,1H), 3.41 (s, 3H), 2.99 (s, 3H), 2.91 (s, 3H), 1.96 (s, 3H), 1.52 (d,J=6.9 Hz, 3H).

Example 1786-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridazine-4-carboxamidebis(2,2,2-trifluoroacetate)

Step 1. 6-chloropyridazine-4-carbonyl chloride

6-oxo-1,6-dihydropyridazine-4-carboxylic acid (0.20 g, 1.4 mmol, ArkPharm, Inc, catalog# AK-26372) was dissolved in phosphoryl chloride (8.0mL, 86 mmol) and DMF (0.080 mL) under nitrogen. The reaction was heatedto 80° C. in an oil bath and monitored by LC/MS. After heating for 3 hthe starting material was consumed (monitored for the methyl ester byadding aliquot to methanol). This reaction mixture was allowed to coolto room temperature and was concentrated in vacuo to remove the residualphosphoryl chloride. The crude product was used in the next step withoutpurification.

Step 2. 6-chloro-N,N-dimethylpyridazine-4-carboxamide

The 6-chloropyridazine-4-carbonyl chloride (0.18 g, 1.04 mmol wasdissolved in methylene chloride (12.0 mL) and a 2.0 M dimethylamine inTHF (1.4 mL) was added at room temperature. The reaction was stirred for1 h and was complete. The reaction was partitioned between EtOAc andwater. The organic layer was washed with 1 N HCl, brine, dried overmagnesium sulfate and concentrated to give the crude product as an amberoil. The product was purified by chromatography on silica gel elutingwith hexane:EtOAc gradient to give6-chloro-N,N-dimethylpyridazine-4-carboxamide as a colorless viscousoil, (0.16 gm, 60%). LCMS calculated for C₇H₉ClN₃O (M+H)⁺: m/z=186.0.found: 185.9.

Step 3.6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridazine-4-carboxamideb is (2,2,2-trifluoroacetate)

Using procedures analogous to Example 177, but using6-chloro-N,N-dimethylpyridazine-4-carboxamide from Example 178, Step 2,the title compound was prepared and purified by prep HPLC on a C-18column eluting with water:acetonitrile gradient buffered to pH 2 withTFA to give6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridazine-4-carboxamideas a white amorphous solid (0.015 g, 20%). LCMS calculated forC₂₂H₂₄ClN₈O₂ (M+H)⁺: m/z=467.2. found: 467.2. ¹H NMR (300 MHz, DMSO-d₆)δ 9.34 (d, J=2.0 Hz, 1H), 8.70 (s, 1H), 8.32 (m, 2H), 7.86 (d, J=2.0 Hz,1H), 7.73 (s, 1H), 5.74 (m, 1H), 3.43 (s, 3H), 3.02 (s, 3H), 2.93 (s,3H), 2.01 (s, 3H), 1.54 (d, J=6.9 Hz, 3H).

Example 1795-{3-chloro-2-cyano-6-ethoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamidebis(2,2,2-trifluoroacetate)

Step 1. 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile

The 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (3.0 g, 11mmol, from Example 187, Step 2) was dissolved in DMF (24 mL) andpotassium cyanide (0.88 g, 13 mmol) was added. The reaction was heatedto 85° C. and monitored by LC/MS. After heating for 18 h the reactionwas complete. The reaction was allowed to cool to room temperature andthen potassium carbonate (3.1 g, 22 mmol) and iodoethane (1.3 mL, 17mmol) were added. The reaction was heated to 60° C. overnight. Afterstirring for 18 h the reaction was complete. The crude was diluted withEtOAc and washed with water, brine, dried over magnesium sulfate andconcentrated to give the crude product as a dark oil. The product waspurified by chromatography on silica gel eluting with hexane:EtOAcgradient to give 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile as anoil which solidified (2.1 g, 62%). LCMS calculated forC₁₁H₁₀BrClNO₂(M+H)⁺: m/z=301.9, 303.9. found: 301.6, 303.6.

Step 2. 4-(1-aminoethyl)-2-bromo-6-chloro-3-ethoxybenzonitrile

Titanium tetraisopropoxide (0.82 mL, 2.8 mmol) was added to a mixture of4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (0.70 g, 2.3 mmol) and2.0 M ammonia in ethanol (5.78 mL) at 0° C. The reaction was heated andstirred at 60° C. under nitrogen for 3 hours. The reaction was allowedto cool to room temperature, cooled in an ice bath and sodiumtetrahydroborate (0.131 g, 3.47 mmol) was added, the solution wasstirred at room temperature for another 2 hours. The reaction mixturewas quenched with 2 M ammonia in water, and was stirred to allow aprecipitate to form. The slurry was filtered and the solid was washedwith EtOAc. The organic solvent was removed under vacuum and the residuewas dissolved in methylene chloride. The organic layer was then washedwith sat'd NaHCO₃, water, brine, dried over MgSO₄, filtered andconcentrated to give4-(1-aminoethyl)-2-bromo-6-chloro-3-ethoxybenzonitrile as an oil (0.7 g,100%). The crude was used in the next step without purification. LCMScalculated for C₁₁H₁₃BrClN₂O (M+H)⁺: m/z=302.9, 304.9. found: 302.9,304.9.

Step 3. tert-butyl[1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate

The 4-(1-aminoethyl)-2-bromo-6-chloro-3-ethoxybenzonitrile (0.7 g, 2.3mmol) was dissolved in 1,4-dioxane (13 mL) and DIPEA (1.3 mL, 7.7 mmol)and the di-tert-butyldicarbonate (0.757 g, 3.47 mmol) was added. Thereaction was allowed to stir at room temperature overnight. The reactionwas complete by LC/MS, and the reaction mixture was diluted with EtOAcand washed with 1 N HCl, brine, dried over magnesium sulfate andconcentrated to give the crude product as an oil. The product waspurified by chromatography on silica gel eluting with hexane: EtOAcgradient to give tert-butyl[1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate as asemi-solid (0.85 g, 90%). LCMS calculated for C₁₁H₁₀BrClNO (M+H)⁺:m/z=285.9, 287.9. found: 285.9, 287.9. This racemic material wasseparated by chiral column HPLC: ChiralPak OJ-H 20×250 mm, 15%ethanol:hexane, 15 mL/min, loading 25 mg/mL to give the separatedenantiomers (Peak 1 retention time: 5.25 min, Peak 2 retention time:6.45 min). The peak 2 enantiomer was used further in synthesis.

Step 4. 5-Bromo-N,N-dimethylpyridine-2-carboxamide

5-Bromopyridine-2-carboxylic acid (20 g, 100 mmol, Frontier Scientificcatalog# B1704) was stirred in methylene chloride (30 mL) and cooled to0° C. 2.0 M Oxalyl chloride in methylene chloride (100 mL) was addedslowly followed by DMF (0.8 mL). Vigorous degassing occurred. Themixture was stirred at 0° C. for 30 min and at rt overnight. The mixturewas evaporated and redissolved in methylene chloride (130 mL).Dimethylamine hydrochloride (9.8 g, 120 mmol) was added and the mixturewas cooled to 0° C. Triethylamine (56.1 mL, 400 mmol) was added slowly(over 5 minutes) which caused significant exotherm and precipitation ofa brown/orange solid. The mixture was stirred at rt for 2 h. The mixturewas diluted with methylene chloride and washed with saturated sodiumbicarbonate, brine, dried over sodium sulfate, filtered and evaporated.Purification on silica gel using ethyl acetate in hexanes (0-60%) gavethe desired compound, (22.0 g, 100%). LCMS calculated for C₈H₁₀BrN₂O(M+H)⁺: m/z=229.0, 231.0. found: 228.9, 230.9.

Step 5. {6-[(Dimethylamino)carbonyl]pyridin-3-yl}boronic acid

A mixture of 5-bromo-N,N-dimethylpyridine-2-carboxamide (23 g, 98 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2]bi[[1,3,2]dioxaborolanyl] (27 g, 110mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (4.8 g, 5.9 mmol),1,1′-bis(diphenylphosphino)ferrocene (3.3 g, 5.9 mmol), and potassiumacetate (30 g, 300 mmol) in 1,4-dioxane (600 mL) was heated at 120° C.for 16 h. The mixture was cooled to rt and diluted with EtOAc. Theorganic solution was washed with saturated ammonium chloride solutionwhich was discarded and then with water (1 L). The water wash wasevaporated to give the desired compound (10 g, 50%). LCMS calculated forC₈H₁₂BN₂O₃ (M+H)⁺: m/z=195.1. found: 195.1.

Step 6. tert-butyl[1-(5-chloro-4-cyano-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxyphenyl)ethyl]carbamate

The tert-butyl[1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (0.05 g, 0.1mmol, Example 179, peak 2) was combined with{6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (0.034 g, 0.17mmol, Example 179, Step 5) in 1,4-dioxane (3.0 mL) and potassiumcarbonate (0.034 g, 0.25 mmol) dissolved in water (1.0 mL) in a tube.The reaction was degassed with nitrogen and thetetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was addedand degassed again. The tube was sealed and heated in an oil bath to 90°C. After heating for 18 h the reaction was complete. This was allowed tocool to room temperature and partitioned between EtOAc and water. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated to give the crude as a dark oil. The product was purifiedby chromatography on silica gel eluting with hexane:EtOAc gradient togive tert-butyl[1-(5-chloro-4-cyano-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxyphenyl)ethyl]carbamateas a viscous oil (0.04 g, 66%). LCMS calculated for C₂₄H₃₀ClN₄O₄ (M+H)⁺:m/z=473.2. found: 473.1.

Step 7.5-{3-[1-aminoethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamidedihydrochloride

The tert-butyl[1-(5-chloro-4-cyano-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxyphenyl)ethyl]carbamatefrom the above step (0.04 g, 0.085 mmol) was treated with 4 M HCl indioxane (4 mL) and stirred at room temperature for 1 hour. The reactionwas concentrated in vacuo to give5-{3-[1-aminoethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamideas a semi-solid residue (0.05 g, 100%). LCMS calculated for C₁₉H₂₂ClN₄O₂(M+H)⁺: m/z=373.1. found: 373.1.

Step 8.5-{3-chloro-2-cyano-6-ethoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamidebis(2,2,2-trifluoroacetate)

The5-{3-[1-aminoethyl]-5-chloro-6-cyano-2-ethoxyphenyl}-N,N-dimethylpyridine-2-carboxamide(0.05 g, 0.1 mmol) was combined with6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.047 g, 0.20 mmol,from Example 176, Step 4) in 2-methoxyethanol (3.0 mL) and DIPEA (0.069mL, 0.39 mmol) in a sealed tube and heated to 105° C. After heating for18 h the reaction was complete. This was allowed to cool to roomtemperature and 4 M HCl in dioxane (3 mL) was added. The reaction wasstirred for 2 h and was complete. This was concentrated in vacuo andpurified by prep HPLC on a C-18 column eluting with water:acetonitrilegradient (buffered to pH 2 with TFA) to give5-{3-chloro-2-cyano-6-ethoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamideas a white amorphous solid (0.020 g, 33%). LCMS calculated forC₂₄H₂₄ClN₈O₂ (M+H)⁺: m/z=491.1. found: 491.1. ¹H NMR (300 MHz, DMSO-d₆)δ 8.75 (s, 1H), 8.53 (m, 1H), 8.33-8.05 (m, 3H), 7.92 (s, 1H), 7.73 (d,J=8.1 Hz, 1H), 5.81 (m, 1H), 4.07-3.89 (m, 1H), 3.42 (m, 1H), 3.04 (s,3H), 2.96 (s, 3H), 1.56 (d, J=6.9 Hz, 3H), 1.00 (t, J=7.0 Hz, 3H).

Example 1806-chloro-3-ethoxy-2-[6-(1-hydroxyethyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrilebis(2,2,2-trifluoroacetate)

Step 1. [6-(1-hydroxyethyl)pyridin-3-yl]boronic acid

1.0 M Methylmagnesium chloride in THF (0.4 mL, 0.4 mmol) was addeddropwise to a mixture of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbaldehyde(50 mg, 0.2 mmol, Frontier Scientific, catalog #F2110) in THF (2 mL) at0° C. After stirring for 1 h at room temperature, the reaction wasquenched with 1 N NH₄Cl and was extracted with EtOAc. The organic layerwas washed with brine, dried over MgSO₄, and concentrated to give thecrude [6-(1-hydroxyethyl)pyridin-3-yl]boronic acid. This was used in thenext step without purification.

Step 2.6-chloro-3-ethoxy-2-[6-(1-hydroxyethyl)pyridin-3-yl]-4-[-1-(9H-purin-6-ylamino)ethyl]benzonitrileb is (2,2,2-trifluoroacetate)

Using procedures analogous to Example 179, but using[6-(1-hydroxyethyl)pyridin-3-yl]boronic acid from Step 1 above, inExample 179 Step 4, the title compound was prepared and purified by prepHPLC on a C-18 column eluting with a water:acetonitrile gradientbuffered to pH 2 with TFA, to give6-chloro-3-ethoxy-2-[6-(1-hydroxyethyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrileas a white amorphous solid (0.011 g, 35%). LCMS calculated forC₂₃H₂₃ClN₇O₂ (M+H)⁺: m/z=464.1. found: 464.0. ¹H NMR (300 MHz, CD₃OD) δ8.74 (d, J=1.8 Hz, 1H), 8.38 (m 2H), 8.29-8.18 (m, 2H), 7.89 (d, J=8.2Hz, 1H), 7.76 (s, 1H), 5.86 (m, 1H), 5.05 (m, J=6.5 Hz, 1H), 4.08-3.87(m, 1H), 3.58-3.43 (m, 1H), 1.70 (d, J=6.9 Hz, 3H), 1.57 (d, J=6.6 Hz,3H), 1.08 (t, J=7.0 Hz, 3H).

Example 181N-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}-9H-purin-6-aminebis(2,2,2-trifluoroacetate)

Step 1. 1-(5-chloro-2-hydroxy-4-methylphenyl)propan-1-one

The 4-chloro-3-methyl-phenol (2 g, 10 mmol) and the propionyl chloride(1.8 mL, 20. mmol) were combined and the mixture was heated at 60° C.for 2 hours. The reaction was concentrated in vacuo to remove excesspropionyl chloride to give an oil. To this was added aluminumtrichloride (2.7 g, 20. mmol) and the mixture was heated at 180° C. for30 minutes. The reaction mixture was then cooled to room temperature andslowly quenched with 1 N HCl while cooling in an ice bath. The reactionwas partitioned between EtOAc and water. The organic layer was washedwith 1 N HCl, water, brine, dried over magnesium sulfate andconcentrated to give the crude product as a dark oil. The product waspurified by chromatography on silica gel eluting with hexane:EtOAcgradient to give 1-(5-chloro-2-hydroxy-4-methylphenyl)propan-1-one as asolid (1.5 g, 60%). LCMS calculated for C₁₀H₁₂ClO₂ (M+H)⁺: m/z=199.0.found: 198.9.

Step 2. 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-one

The 1-(5-chloro-2-hydroxy-4-methylphenyl)propan-1-one (1.6 g, 8.0 mmol)was dissolved in acetic acid (20.0 mL) and N-bromosuccinimide (1.7 g,9.7 mmol) was added. The reaction was warmed in an oil bath to 65° C.and monitored by LC/MS. After heating for 3 h the reaction was complete.This was allowed to cool to room temperature and was concentrated invacuo. The residue was diluted with EtOAc and washed with water (twice),brine, dried over magnesium sulfate and concentrated to give1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)propan-1-one as an amberoil. This oil was dissolved in DMF (10.0 mL) and potassium carbonate(3.3 g, 24 mmol) and methyl iodide (0.75 mL, 12 mmol) were added. Thereaction was stirred at 65° C. for 18 hours. The reaction was complete,and the reaction mixture was diluted with EtOAc, washed with water,brine, dried over magnesium sulfate and concentrated to give the crudeproduct as a dark oil. The product was purified by chromatography onsilica gel eluting with a hexane: EtOAc gradient to give1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-one as an oil (1.8g, 81%). LCMS calculated for C₁₁H₁₃BrClO₂ (M+H)⁺: m/z=290.9, 292.9.found: 290.8, 292.9.

Step 3. tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate

Titanium tetraisopropoxide (3.0 mL, 10 mmol) was added to a mixture of1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-one (2.5 g, 8.6mmol) and 2.0 M ammonia in ethanol (21.4 mL) at 0° C. The reaction washeated and stirred at 60° C. under nitrogen for 3 hours. The reactionwas allowed to cool to room temperature, cooled in an ice bath and thesodium tetrahydroborate (0.486 g, 12.9 mmol) was added, the solution wasstirred at room temperature for another 2 hours. The reaction mixturewas quenched with 2 M ammonia in water, and was stirred to form theprecipitate. The slurry was filtered, the solids were washed with EtOAcand the organic layer was concentrated in vacuo. The residue was dilutedwith methylene chloride, washed with sat'd NaHCO₃, water, brine, driedover MgSO₄, filtered and concentrated to give1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propan-1-amine as an oil.This was diluted with 1,4-dioxane (48 mL) and DIPEA (5.0 mL) and thedi-tert-butyldicarbonate (2.81 g, 12.9 mmol) was added. The reaction wasallowed to stir at room temperature overnight. The reaction was completeby LC/MS, and the reaction mixture was diluted with EtOAc and washedwith 1 N HCl, brine, dried over magnesium sulfate and concentrated togive the crude product as an oil. The product was purified bychromatography on silica gel eluting with a hexane: EtOAc gradient togive tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate as asemisolid (2.0 g, 80%). LCMS calculated for C₁₁H₁₃BrClO (M+H)⁺:m/z=274.9, 276.9. found: 274.9, 276.8. This racemic material wasseparated by chiral column HPLC: ChiralPak AD-H 20×250 mm, 3%ethanol:hexane, 18 mL/min, loading 10 mg/mL, to give the separatedenantiomers. Peak 2 tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate was usedfurther in synthesis.

Step 4. tert-butyl{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}carbamate

The tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)propyl]carbamate peak 2(0.075 g, 0.19 mmol) was combined with3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.081g, 0.29 mmol, Frontier Scientific, catalog #F2018) in 1,4-dioxane (4.6mL) and potassium carbonate (0.053 g, 0.38 mmol) in water (1.5 mL) in atube. This was degassed with nitrogen and thetetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol) was added.The reaction was degassed with nitrogen, sealed and heated to 90° C. inan oil bath. The reaction was complete after 18 h, and the reactionmixture was allowed to cool and partitioned between EtOAc and water. Theorganic layer was washed with brine, dried over magnesium sulfate andconcentrated to give the crude product as an oil. The product waspurified by chromatography on silica gel eluting with a hexane:EtOAcgradient to give tert-butyl{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}carbamateas a viscous oil (0.05 g, 77%). LCMS calculated for C₂₁H₂₇ClFN₂O₃(M+H)⁺: m/z=409.1. found: 409.1.

Step 5.1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propan-1-aminedihydrochloride

The tert-butyl{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}carbamate(0.05 g, 0.12 mmol) was diluted with 4 M HCl in dioxane (4 mL) and wasstirred at room temperature for 1 hour. The reaction was complete andthe reaction mixture was concentrated to give1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propan-1-amineas a semi-solid (100%). LCMS calculated for C₁₆H₁₆ClFNO (M+H)⁺:m/z=292.0. found: 292.0.

Step 6.N-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}-9H-purin-6-aminebis(2,2,2-trifluoroacetate)

The 1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methy1-phenyl]propan-1-amine (0.030 g, 0.097 mmol) was combined with6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.035 g, 0.14 mmol,from Example 176, Step 4) in 2-methoxyethanol (2.0 mL) and DIPEA (0.051mL, 0.29 mmol) in a sealed tube. The reaction was heated to 105° C.After heating overnight, the reaction was allowed to cool to roomtemperature and was treated with 4 M HCl in dioxane (3.0 mL) at roomtemperature. After stirring for 2 h the reaction was concentrated invacuo to give a residue that was purified by prep HPLC on C-18 columneluting with a water:acetonitrile gradient buffered to pH 2 with TFA togiveN-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}-9H-purin-6-amineas a white amorphous solid (0.012 g, 50%). LCMS calculated for C₂₁H₂₁ClFN₆O (M+H)⁺: m/z=427.1. found: 427.16. ¹H NMR (300 MHz, DMSO-d₆) δ 8.90(m, 1H), 8.65 (d, J=2.1 Hz, 1H), 8.38 (m, 3H), 7.82 (d, J=26.1 Hz, 1H),7.67 (s, 1H), 5.57 (m, 1H), 339 (s, 3H), 2.03 (s, 3H), 1.99-1.76 (m,2H), 0.95 (t, J=7.3 Hz, 3H).

Example 182N-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}propyl)-9H-purin-6-aminebis(2,2,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 181, butusing3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(Peptech, catalog# BE358) in Step 4. The product was purified by prepHPLC on a C-18 column eluting with water:acetonitrile gradient bufferedto pH 2 with TFA to giveN-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}propyl)-9H-purin-6-amineas white amorphous solid (0.012 g, 30%). LCMS calculated forC₂₂H₂₄ClN₆O₃S (M+H)⁺: m/z=487.1. found: 487.0. ¹H NMR (300 MHz, DMSO-d₆)δ 9.12 (s, 1H), 8.87 (m, 2H), 8.32 (m, 3H), 7.71 (s, 1H), 5.57 (m, 1H),3.39 (s, 6H), 2.05 (s, 3H), 1.91 (m, 2H), 0.96 (t, J=7.3 Hz, 3H).

Example 183(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)methanolbis(2,2,2-trifluoroacetate)

Step 1. tert-butyl{1-[5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate

To a mixture of tert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate (200 mg,0.5 mmol, from Example 113, Step 1 peak 2) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbaldehyde(150 mg, 0.63 mmol, Frontier Scientific, catalog# F2110) in 1,4-dioxane(4 mL) was added potassium carbonate (200 mg, 2 mmol) in water (2 mL).The reaction was degassed with N₂ andtetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) was addedand degassed again with N₂. The reaction was heated at 100° C.overnight. The reaction was allowed to cool to room temperature and waspartitioned between water and EtOAc. The organic layer was washed withbrine, dried over MgSO₄, filtered and concentrated to give the crudeproduct. The product was purified by chromatography on silica geleluting with a hexane:EtOAc gradient to give tert-butyl{1-[5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamateas a yellow oil (0.15 g, 70%). LCMS calculated for C₂₁H₂₆ClN₂O₄(M+H)⁺:m/z=405.2. found: 405.1.

Step 2. tert-butyl(1-{5-chloro-3-[6-(hydroxymethyl)pyridin-3-yl]-2-methoxy-4-methylphenyl}ethyl)carbamate

Sodium tetrahydroborate (2.8 mg, 0.074 mmol) was added to a mixture oftert-butyl{1-[5-chloro-3-(6-formylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate(20 mg, 0.05 mmol) in methanol (2 mL) at 0° C. The reaction was stirredfor 1 h at 0° C. The reaction mixture was partitioned between water andEtOAc. The combined organic layers was washed with brine, dried overMgSO₄, filtered and concentrated to give crude product. This crude wasused for next step.

Step 3.(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)methanolbis(2,2,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 177starting with Step 5, but using tert-butyl(1-{5-chloro-3-[6-(hydroxymethyl)pyridin-3-yl]-2-methoxy-4-methylphenyl}ethyl)carbamatefrom Step 2 above to give the crude product. The reaction product waspurified on prep HPLC on a C-18 column eluting with a water:acetonitrilegradient buffered with TFA to give(5-[3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl]pyridin-2-yl)methanolas a white amorphous solid (0.005 g, 20%). LCMS calculated forC₂₁H₂₂CN₆O₂(M+H)⁺: m/z=425.2. found: 425.1. ¹H NMR (500 MHz, CD₃OD) δ8.54 (s, 1H), 8.37 (s, 1H), 8.27 (s, 1H), 8.09 (bs, 1H), 7.85 (d, J=8.1Hz, 1H), 7.62 (s, 1H), 5.86 (m, 1H), 4.91 (s, 2H), 3.48 (s, 3H), 2.18(s, 3H), 1.70 (d, J=6.9 Hz, 3H).

Example 1842-(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)propan-2-olbis(2,2,2-trifluoroacetate)

Step 1. 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide

N,O-dimethylhydroxylamine hydrochloride (500 mg, 5 mmol) was added to amixture of N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1400 mg, 3.7 mmol), DIPEA (1000 μL, 7 mmol) and5-bromopyridine-2-carboxylic acid (500 mg, 2 mmol, Frontier Scientificcatalog# B1704) in DMF (10 mL) at room temperature. The reaction wasstirred overnight and was partitioned between water and EtOAc. Thecombined organic layer was washed with brine, dried over MgSO₄, filteredand concentrated to give the crude product. The product was purified bychromatography on silica gel eluting with a hexane:EtOAc gradient togive 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide as a clear oil(0.5 g, 60%). LCMS calculated for C₈H₁₀BrN₂O₂(M+H)⁺: m/z=244.9, 246.9.found: 244.9, 246.9.

Step 2. 1-(5-bromopyridin-2-yl)ethanone

3.0 M Methylmagnesium chloride in THF (0.5 mL) was added dropwise to amixture of 5-bromo-N-methoxy-N-methylpyridine-2-carboxamide (200 mg, 0.8mmol) in THF (10 mL) at 0° C. After stirring for 1 h at roomtemperature, the reaction was quenched with 1 N NH₄Cl and was extractedwith EtOAc. The combined organic layer was washed with brine and driedover MgSO₄, concentrated to give the crude product (0.15 g, 90%). Thiswas used in the next step without purification. LCMS calculated forC₇H₇BrNO (M+H)⁺: m/z=199.9, 201.9. found: 199.9, 201.9.

Step 3. 2-(5-bromopyridin-2-yl)propan-2-ol

3.0 M Methylmagnesium chloride in THF (0.3 mL) was added dropwise to amixture of 1-(5-bromopyridin-2-yl)ethanone (100 mg, 0.5 mmol) in THF (10mL) at 0° C. After stirring for 1 h at room temperature, the reactionwas quenched with 1 N NH₄Cl and was extracted with EtOAc. The combinedorganic layer was washed with brine and dried over MgSO₄, concentratedto give crude product (0.1 g, 100%). Crude was used in next step withoutpurification. LCMS calculated for C₈H₁₁BrNO (M+H)⁺: m/z=215.9, 217.9.found: 215.8, 217.8.

Step 4.2-(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)propan-2-olbis(2,2,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 177, butusing 2-(5-bromopyridin-2-yl)propan-2-ol from Step 3 above to give thecrude product. The reaction product was purified by prep HPLC on a C-18column eluting with a water:acetonitrile gradient buffered with TFA togive2-(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)propan-2-olas a white amorphous solid (0.005 g, 20%). LCMS calculated forC₂₃H₂₆ClN₆O₂(M+H)⁺: m/z=453.1. found: 453.0. ¹H NMR (300 MHz, DMSO-d₆) δ8.85 (m, 1H), 8.42 (m, 3H), 7.86 (m, 2H), 7.64 (s, 1H), 5.75 (m, 1H),3.36 (s, 3H), 2.03 (s, 3H), 1.55 (d, J=6.9 Hz, 3H), 1.51 (s, 6H).

Example 185N-(1-{5-chloro-2-methoxy-3-[6-(1-methoxy-1-methylethyl)pyridin-3-yl]-4-methylphenyl}ethyl)-9H-purin-6-aminebis(2,2,2-trifluoroacetate)

Step 1. 5-bromo-2-(1-methoxy-1-methylethyl)pyridine

2-(5-bromopyridin-2-yl)propan-2-ol (50 mg, 0.2 mmol, from Example 184,Step 3) was added to a mixture of NaH in mineral oil (10 mg, 0.5 mmol)in DMF (5 mL). The reaction was stirred for 30 min and the methyl iodide(30 μL, 0.5 mmol) was added and stirred for 2 hours. The reaction waspartitioned between EtOAc and water. The combined organic layer waswashed with brine, dried over MgSO₄, filtered and concentrated to givecrude product 5-bromo-2-(1-methoxy-1-methylethyl)pyridine as an oil(0.05 g, 90%). LCMS calculated for C₉H₁₃BrNO (M+H)⁺: m/z=230.0, 232.0.found: 230.0, 231.8.

Step 2.N-(1-{5-chloro-2-methoxy-3-[6-(1-methoxy-1-methylethyl)pyridin-3-yl]-4-methylphenyl}ethyl)-9H-purin-6-aminebis(2,2,2-trifluoroacetate)

The title compound was prepared by methods analogous to Example 177, butusing 5-bromo-2-(1-methoxy-1-methylethyl)pyridine from Step 1 above togive the crude product. The reaction product was purified by prep HPLCon a C-18 column eluting with a water:acetonitrile gradient bufferedwith TFA to giveN-(1-[5-chloro-2-methoxy-3-[6-(1-methoxy-1-methylethyl)pyridin-3-yl]-4-methylphenyl]ethyl)-9H-purin-6-amineas a white amorphous solid (0.005 g, 30%). LCMS calculated forC₂₄H₂₈ClN₆O₂(M+H)⁺: m/z=467.2. found: 467.1. ¹H NMR (300 MHz, DMSO-d₆) δ9.30 (m, 1H), 8.50 (m, 3H), 7.84 (m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.62(s, 1H), 5.76 (m, 1H), 3.31 (s, 3H), 3.10 (s, 3H), 2.04 (s, 3H), 1.57(d, J=6.8 Hz, 3H), 1.52 (s, 6H).

Example 1863-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrilebis(2,2,2-trifluoroacetate)

Step 1. tert-butyl(1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate

To tert-butyl[-1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (50 mg, 0.1mmol, from Example 179, Step 3) and3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(30. mg, 0.11 mmol, Peptech, catalog #BE358) in 1,4-dioxane (4 mL) wasadded potassium carbonate (30 mg, 0.2 mmol) in water (2 mL). Thereaction was degassed with N₂. Tetrakis(triphenylphosphine)palladium(0)(40 mg, 0.04 mmol) was added and degassed again with N₂. The reactionwas heated at 100° C. overnight. The reaction was allowed to cool toroom temperature and was partitioned between EtOAc and water. Thecombined organic layer was washed with brine, dried over MgSO₄, filteredand concentrated to give crude product. The product was purified bychromatography on silica gel eluting with a hexane:EtOAc gradient togive tert-butyl(1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamateas a yellow oil (0.030 g, 60%). LCMS calculated for C₂₂H₂₇ClN₃O₅S(M+H)⁺: m/z=480.1. found: 480.1.

Step 2. tert-butyl(1-{4-cyano-2-ethoxy-5-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate

To tert-butyl(1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate(60 mg, 0.1 mmol) and methylboronic acid (6.4 mg, 0.11 mmol) in1,4-dioxane (4 mL) was added sodium carbonate (20 mg, 0.2 mmol) in water(2 mL). The reaction was degassed with N₂.Dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium(4 mg, 0.005 mmol) was added and degassed again with N₂. The reactionwas heated at 90° C. overnight. The reaction was allowed to cool to roomtemperature and was partitioned between EtOAc and water. The combinedorganic layer was washed with brine, dried over MgSO₄, filtered andconcentrated to give crude product. The product was purified bychromatography on silica gel eluting with a hexane: EtOAc gradient togive tert-butyl(1-{4-cyano-2-ethoxy-5-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamateas a yellow oil (0.030 g, 50%). LCMS calculated for C₂₃H₃₀N₃O₅S (M+H)⁺:m/z=460.1. found: 460.2.

Step 3.4-(−1-aminoethyl)-3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitriledihydrochloride

The tert-butyl(1-{4-cyano-2-ethoxy-5-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate(0.030 gm, 0.065 mmol) was dissolved in 4.0 M HCl in dioxane (2 mL) andwas stirred for 1 hour. The reaction was concentrated in vacuo to give4-(1-aminoethyl)-3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrileas a semi-solid (0.035 g, 100%). LCMS calculated for C₁₈H₂₂N₃O₃S (M+H)⁺:m/z=360.1. found: 360.2.

Step 4.3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[(1S)-1-(9H-purin-6-ylamino)ethyl]benzonitrilebis(2,2,2-trifluoroacetate)

6-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (35 mg, 0.15 mmol, fromExample 176, Step 4) and DIPEA (0.04 mL, 0.2 mmol) were added to4-(1-aminoethyl)-3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]benzonitrilein ethanol (2 mL). The reaction was heated to 120° C. overnight. Thereaction was allowed to cool to room temperature and was concentrated invacuo to give3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)benzonitrileas a solid residue. This intermediate was dissolved in 4.0 M HCl indioxane (1 mL) and was stirred for 10 minutes. The reaction wasconcentrated and was purified on prep HPLC on a C-18 column eluting withwater:acetonitrile gradient buffered with TFA to give3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrileas a white solid (0.010 g, 16%). LCMS calculated for C₂₃H₂₄N₇O₃S (M+H)⁺:m/z=478.1. found: 478.1. ¹H NMR (300 MHz, DMSO-d₆) δ 9.18 (d, J=2.2 Hz,1H), 9.09 (d, J=2.0 Hz, 1H), 8.75 (m, 1H), 8.54 (t, J=2.1 Hz, 1H), 8.33(m, 2H), 7.68 (s, 1H), 5.80 (m, 1H), 3.99-3.79 (m, 1H), 3.40 (s, 3H),3.34 (m, 1H), 2.47 (s, 3H), 1.58 (d, J=6.9 Hz, 3H), 0.98 (t, J=6.9 Hz,3H).

Example 187N-{1-[5-Chloro-4-fluoro-2-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]ethyl}-9H-purin-6-aminehydrochloride

Step 1. 1-(5-Chloro-4-fluoro-2-hydroxyphenyl)ethanone

Acetyl chloride (3.6 mL, 51 mmol) was added to 4-chloro-3-fluorophenol(5.1 g, 35 mmol) and the resulting mixture was heated at 60° C. for 2hours. Aluminum trichloride (7.0 g, 52 mmol) was added and the mixturewas heated at 180° C. for 30 minutes. The mixture was cooled to roomtemperature. The mixture was cooled to 0° C. and 1 N HCl solution (100mL) was added dropwise over 30 minutes. The precipitate was washed wellwith water and dried under vacuum to give the desired compound (6.6 g,100%).

Step 2. 1-(3-Bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone

To a stirred solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone(8.0 g, 42 mmol) in acetic acid (80 mL) was added N-bromosuccinimide(9.0 g, 50 mmol) and the resulting mixture was stirred at roomtemperature for 18 hours. The reaction mixture was concentrated,neutralized with saturated sodium bicarbonate solution and extractedwith EtOAc. The combined organic layers were washed with brine, driedover sodium sulfate, and then concentrated to dryness under reducedpressure. The residue was purified on silica gel, eluting with 0 to 20%EtOAc in hexane, to yield the desired product (10.5 g, 93%). LCMScalculated for C₈H₆BrClFO₂ (M+H)⁺: m/z=266.9, 268.9. found: 267.1,269.1.

Step 3. 1-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone

A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (4.8g, 18 mmol), potassium carbonate (6.5 g, 47 mmol) and methyl iodide (2.5mL, 40 mmol) in DMF (10 mL) was heated at 60° C. for 1 hour. The mixturewas diluted with water and extracted with EtOAc. The combined organiclayers were washed with brine, dried over sodium sulfate, andevaporated. The residue was purified on silica gel, eluting with 0 to20% EtOAc in hexane, to yield the desired compound (2.2 g, 44%). LCMScalculated for C₉H₈BrClFO₂ (M+H)⁺: m/z=280.9, 282.9. found: 281.0,283.0.

Step 4. 1-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanol

To a solution of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanone(3.8 g, 14 mmol) in methanol (30 mL, 800 mmol) was added sodiumtetrahydroborate (0.83 g, 22 mmol) at 0° C. The mix was stirred at 0° C.for 1 hour. Water (10 mL) was added to the mixture. The mixture wasconcentrated to about 30 mL. The residue was diluted with EtOAc, washedwith water and brine, dried over magnesium sulfate and evaporated toyield the desired compound (3.9 g, 100%). LCMS calculated for C₉H₈BrClFO(M−OH)⁺: m/z=264.9, 266.9. found: 265.0, 267.0.

Step 5. 1-(1-azidoethyl)-3-bromo-5-chloro-4-fluoro-2-methoxybenzene

To a solution of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanol(3.9 g, 14 mmol) in methylene chloride (42 mL), cooled at 0° C. wasadded DIPEA (4.0 mL, 23 mmol) followed by methanesulfonyl chloride (1.6mL, 20 mmol). The mixture was stirred for 1 h at 0° C. Water (100 mL)was added while cold. The organic layer was separated, washed withbrine, dried over magnesium sulfate and concentrated to give1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl methanesulfonate. Themesylate was dissolved in DMF (41 mL) and sodium azide (1.8 g, 27 mmol)was added. The reaction was stirred for 2 hours. The reaction mixturewas diluted with EtOAc and washed with saturated sodium bicarbonatesolution, water and brine, dried over magnesium sulfate andconcentrated. Purification on silica gel using 0-30% EtOAc in hexanegave the desired compound (3.3 g, 78%). LCMS calculated for C₉H₈BrClFO(M−N₃)⁺: m/z=264.9, 266.9. found: 265.0, 267.0.

Step 6. 1-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanamine

To the stirred solution of1-(1-azidoethyl)-3-bromo-5-chloro-4-fluoro-2-methoxybenzene (3.3 g, 11mmol) in THF (50 mL) and water (10 mL) was added 1.0 Mtrimethylphosphine in THF (13 mL) at room temperature and the mixturewas stirred for 1 hour. The mixture was diluted with EtOAc, washed withsaturated sodium bicarbonate solution, water, brine, dried overmagnesium sulfate and concentrated to give the desired compound (2.9 g,95%). LCMS calculated for C₉H₈BrClFO (M−NH₂)⁺: m/z=264.9, 266.9. found:265.0, 267.0.

Step 7.N-[1-(3-Bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

A mix of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanamine (1.6 g,5.7 mmol) 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (2.0 g, 8.5mmol, from Example 176, Step 4) and DIPEA (3.0 mL, 17 mmol) in ethanol(30 mL) was heated at 100° C. overnight. The reaction mixture was cooledand poured into saturated sodium bicarbonate solution, extracted intoEtOAc, washed with water, brine, dried over magnesium sulfate andconcentrated. Purification on silica gel using 0-65% EtOAc gave thedesired compound (2.8 g, 100%). LCMS calculated for C₁₉H₂₁BrClFN₅O₂(M+H)⁺: m/z=484.1, 486.1. found: 484.0, 486.0.

Step 8. tert-butyl4-{3-chloro-2-fluoro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate

Into a microwave vial was addedN-[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(85 mg, 0.17 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate(65 mg, 0.21 mmol, Aldrich #706531), sodium carbonate (420 μL, 0.44mmol), 1,4-dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0)(12 mg, 0.010 mmol). The mixture was bubbled with nitrogen for 5 min andheated at 90° C. overnight. The mixture was diluted with water,extracted with EtOAc, dried over magnesium sulfate and concentrated.Purification on silica gel using 0-100% EtOAc in hexane gave the desiredcompound (47 mg, 46%). LCMS calculated for C₂₉H₃₇ClFN₆O₄ (M+H)⁺:m/z=586.3. found: 587.2.

Step 9.N-{1-[5-Chloro-4-fluoro-2-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]ethyl}-9H-purin-6-aminehydrochloride

Into a microwave vial was added tert-butyl4-{3-chloro-2-fluoro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate(10.5 mg, 0.021 mmol) and 4.0 M HCl in 1,4-dioxane (1.0 mL). The mixturewas stirred for 30 min and evaporated. Methylene chloride (1.0 mL) andDIPEA (15.6 μL, 0.090 mmol) were added followed by methanesulfonylchloride (4.8 pt, 0.063 mmol). The mixture was stirred for 15 minutes.The solvents were evaporated. 1 N sodium hydroxide solution (1.0 mL) andmethanol (1.0 mL) were added and the mixture was stirred for 1 hour. Thesolvents were evaporated and purification by preparative LC/MS (pH 10)gave the desired compound (4.0 mg, 40%). LCMS calculated forC₂₀H₂₃ClFN₆O₃S (M+H)⁺: m/z=481.1. found: 481.0. ¹H NMR (DMSO-d₆, 500MHz) δ 12.88 (1H, br s), 8.18 (2H, m), 7.63 (1H, m), 5.91 (1H, m), 5.78(1H, br s), 3.94 (5H, m), 3.40 (2H, m), 2.98 (3H, s), 2.55 (2H, m), 2.39(2H, m), 1.42 (3H, m).

Example 188N-{1-[5-Chloro-4-fluoro-2-methoxy-3-(morpholin-4-ylmethyl)phenyl]ethyl}-9H-purin-6-amine

Step 1.N-[1-(5-Chloro-4-fluoro-2-methoxy-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

To a solution ofN-[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(50 mg, 0.10 mmol, from Example 187, Step 7) in water (0.21 mL) wasadded 1,2-dimethoxyethane (0.7 mL), potassium carbonate (14 mg, 0.10mmol), pyridine:trivinylboroxin (1:1) (26 mg, 0.10 mmol) andtetrakis(triphenylphosphine)Pd(0) (5.2 mg, 0.0045 mmol). The mixture wasbubbled with nitrogen for five min and heated at 80° C. overnight. Thereaction was diluted with water and EtOAc. The combined organic layerswere washed with brine, dried over sodium sulfate and concentrated.Purification on silica gel using 0-100% EtOAc in hexane gave the desiredcompound (29 mg, 60%). LCMS calculated for C₂₁H₂₄ClFN₅O₂ (M+H)⁺:m/z=432.2. found: 432.1.

Step 2.3-Chloro-2-fluoro-6-methoxy-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)benzaldehyde

N-[1-(5-Chloro-4-fluoro-2-methoxy-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(240 mg, 0.56 mmol) was dissolved in THF (10 mL) and 0.16 M osmiumtetraoxide in water (700 μL) was added. Sodium metaperiodate (360 mg,1.7 mmol) and water (1 mL, 60 mmol) were added. The reaction was stirredat 60° C. for 2 hours. Reagents were doubled. 0.16 M osmium tetraoxidein water (700 μL) was added. Sodium metaperiodate (360 mg, 1.7 mmol) andwater (1 mL) were added and the mixture was warmed to 60° C. for another2 hours. The mixture was evaporated and the solids were extracted withdichloromethane. The extracts were purified on silica gel using 0-60%EtOAc in hexanes to give the desired compound (50 mg, 20%). LCMScalculated for C₂₀H₂₂ClFN₅O₃ (M+H)⁺: m/z=434.1. found: 434.1.

Step 3.N-{1-[5-Chloro-4-fluoro-2-methoxy-3-(morpholin-4-ylmethyl)phenyl]ethyl}-9H-purin-6-amine

A mixture of3-chloro-2-fluoro-6-methoxy-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)benzaldehyde(10 mg, 0.023 mmol), in THF (0.95 mL) was stirred at 40° C. for 1 hour.Sodium triacetoxyborohydride (15 mg, 0.069 mmol) and acetic acid (50 μL,0.88 mmol) were added and the mixture was stirred at 40° C. overnight.Morpholine (20 μL, 0.23 mmol) and sodium cyanoborohydride (14 mg, 0.23mmol) were added and the mixture was heated at 40° C. for 1 hour. Thesolvents were stripped down and few drops of trifluoroacetic acid/THFsolution (1:1) were added and the mixture stirred for 30 minutes. Themixture was treated with 6.0 M HCl in water (0.5 mL, 3 mmol) for 30minutes. Purification by preparative LCMS (pH 10) gave the desiredcompound (3.4 mg, 35%). LCMS calculated for C₁₉H₂₃ClFN₆O₂ (M+H)⁺:m/z=421.2. found: 421.1. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.91 (1H, br s),8.17 (2H, m), 7.72 (1H, m), 5.89 (1H, br s), 4.05 (3H, s), 3.50 (7H, m),2.41 (4H, m), 1.42 (3H, m).

Example 1895-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3-isopropyl-1,3-oxazolidin-2-onetrifluoroacetate

Step 1.tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamate

To a solution oftert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate(80 mg, 0.20 mmol) (Example 113, Step 1; peak 2 from chiral separation)in water (0.44 mL) was added 1,2-dimethoxyethane (1.0 mL), potassiumcarbonate (29 mg, 0.21 mmol), pyridine:trivinylboroxin (1:1) (80 mg,0.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (11 mg, 0.0092mmol). The resulting suspension was heated at 80° C. overnight. Thereaction was diluted with water and EtOAc. The aqueous phase wasextracted with EtOAc once. The combined organic solutions were washedwith brine, dried over sodium sulfate and concentrated. The residue waspurified on silica gel using 0-100% EtOAc in hexane to give the desiredcompound (68 mg, 100%). LCMS calculated for C₁₂H₁₄ClO (M−NHBoc)⁺:m/z=209.1. found: 209.0.

Step 2.N-[1-(5-Chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamatewas stirred in 4 N HCl (1.0 mL) for 30 min and evaporated to give1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanamine hydrochloride(480 mg, 1.8 mmol) which was stirred in 1-butanol (86 mL), with DIPEA(1.6 mL, 9.1 mmol) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(650 mg, 2.7 mmol, from Example 176, Step 4). The reaction mixture washeated at 120° C. for 2 hours. The reaction mixture was cooled to roomtemperature and extracted with EtOAc. The extracts were washed withbrine and evaporated. Purification on silica gel using 0-50% EtOAc inhexane gave the desired compound (780 mg, 100%). LCMS calculated forC₂₂H₂₇ClN₅O₂ (M+H)⁺: m/z=428.2. found: 428.1.

Step 3.N-[1-(5-Chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

N-[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(740 mg, 1.7 mmol) was stirred in methylene chloride (5.7 mL) andm-chloroperbenzoic acid (2.1 g, 8.7 mmol) was added. The mixture wasstirred overnight. The suspension was filtered and the solids werewashed with dichloromethane. Evaporation of the filtrates gave thedesired compound.

Step 4.1-[3-Chloro-6-methoxy-2-methyl-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-2-(isopropylamino)ethanol

N-[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(140.0 mg, 0.32 mmol) was stirred in methylene chloride (1.1 mL).Isopropylamine (124 μL, 1.6 mmol) and DIPEA (282 pt, 1.62 mmol) wereadded. The mixture was stirred at 80° C. overnight. Methanol was addedand purification by preparative LC/MS (pH 10) gave the desired compound(12.9 mg, 8%). LCMS calculated for C₂₅H₃₆ClN₆O₃ (M+H)⁺: m/z=503.3.found: 503.1.

Step 5.5-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3-isopropyl-1,3-oxazolidin-2-onetrifluoroacetate

To a solution of1-[3-chloro-6-methoxy-2-methyl-5-((1S)-1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]-2-(ispropylamino)ethanol(7.0 mg, 0.014 mmol) in THF (0.2 mL, 2 mmol), N,N-carbonyldiimidazole(3.1 mg, 0.019 mmol) was added and the mixture was heated at 70° C. for1 hour. The solvents were evaporated. 4.0 M HCl in 1,4-dioxane (1.0 mL)was added and the mixture was stirred for 30 minutes. Evaporation andpurification by preparative LC/MS (pH 2) gave the desired compound (2.0mg, 37%). LCMS calculated for C₂₁H₂₆ClN₆O₃ (M+H)⁺: m/z=445.2. found:445.1.

Example 1901-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-2-morpholin-4-ylethanolbis(trifluoroacetate)

Step 1.tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]carbamate

tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamate(460 mg, 1.4 mmol, from Example 189, Step 1) was stirred in methylenechloride (4.6 mL) and m-chloroperbenzoic acid (2.1 g, 8.5 mmol) wasadded. The mixture was stirred overnight at room temperature. Thesuspension was filtered and the collected solids were washed withmethylene chloride. The filtrates were evaporated to give the desiredcompound.

Step 2.1-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-2-morpholin-4-ylethanolhydrochloride

tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]carbamate(100.0 mg, 0.29 mmol) was stirred in ethanol (2.00 mL, 34 mmol), withmorpholine (130 mg, 1.5 mmol) and DIPEA (260 μL, 1.5 mmol). The mixturewas stirred at 80° C. over the weekend. Purification by preparativeLC/MS (pH 10) gave the Boc intermediate. LCMS calculated forC₂₁H₃₄ClN₂O₅ (M−NH₂)⁺: m/z=429.2. found: 429.2. 4 N HCl (3.0 mL) wasadded and the mixture stirred for 30 minutes. Evaporation gave thedesired compound as the hydrochloride salt (8.8 mg, 8%).

Step 3.1-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-2-morpholin-4-ylethanolbis(trifluoroacetate)

To a solution of1-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}-2-morpholin-4-ylethanolhydrochloride (4.6 mg, 0.014 mmol) in 1-butanol (0.67 mL), DIPEA (12 pt,0.071 mmol) was added followed by6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (5.1 mg, 0.021 mmol,from Example 176, Step 4) and the reaction mixture was heated at 120° C.for 1 hour. The reaction mixture was cooled to room temperature and 4.0M HCl in 1,4-dioxane (0.34 mL) was added. The mixture was stirred for 30minutes. Purification by preparative LC/MS (pH 2) gave the desiredcompound (3.6 mg, 45%). LCMS calculated for C₂₁H₂₈ClN₆O₃ (M+H)⁺:m/z=447.2. found: 447.1

Example 1916-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-4-isopropylmorpholin-3-onetrifluoroacetate

Step 1. tert-Butyl(1-{5-chloro-3-[1-hydroxy-2-(isopropylamino)ethyl]-2-methoxy-4-methylphenyl}ethyl)carbamate

tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-oxiran-2-ylphenyl)ethyl]carbamate(100 mg, 0.29 mmol, from Example 190, Step 1) was stirred in ethanol(2.0 mL, 34 mmol), 2-propanamine (120 μL, 1.5 mmol) and DIPEA (260 μL,1.5 mmol) was added. The mixture was stirred at 80° C. over the weekend.Purification by preparative LC/MS (pH 10) gave the desired compound (5.7mg, 5%). LCMS calculated for C₂₀H₃₄ClN₂O₄ (M+H)⁺: m/z=401.2. found:401.1.

Step 2.tert-Butyl[1-(5-chloro-3-{2-[(chloroacetyl)(isopropyl)amino]-1-hydroxyethyl}-2-methoxy-4-methylphenyl)ethyl]carbamate

To a solution of tert-butyl1-{5-chloro-3-[1-hydroxy-2-(isopropylamino)ethyl]-2-methoxy-4-methylphenyl}ethyl)carbamate(17 mg, 0.041 mmol) in methylene chloride (0.5 mL), triethylamine (17μL, 0.12 mmol) was added followed by the addition of chloroacetylchloride (3.9 μL, 0.049 mmol). The reaction mixture was stirred at roomtemperature for 30 minutes. Purification by preparative LC/MS (pH 10)gave the desired compound (17 mg, 100%). LCMS calculated forC₂₂H₃₄Cl₂N₂O₅Na (M+Na)⁺: m/z=499.2. found: 499.2.

Step 3. tert-Butyl{1-[5-chloro-3-(4-isopropyl-5-oxomorpholin-2-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate

To a solution oftert-butyl[1-(5-chloro-3-{2-[(chloroacetyl)(isopropyl)amino]-1-hydroxyethyl}-2-methoxy-4-methylphenyl)ethyl]carbamate(22 mg, 0.047 mmol) in THF (1.0 mL) cooled at 0° C., sodium hydride (3.6mg, 0.094 mmol; 60% dispersion in mineral oil) was added and the mixturewas stirred for 1 hour. The mixture was quenched with water andextracted with EtOAc. The combined extracts were washed with brine,dried over sodium sulfate, and concentrated to give the desired compound(20 mg, 97%). LCMS calculated for C₂₂H₃₃ClN₂O₅Na (M+Na)⁺: m/z=463.2.found: 463.1.

Step 4.6-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-4-isopropylmorpholin-3-onetrifluoroacetate

To tert-butyl{1-[5-chloro-3-(4-isopropyl-5-oxomorpholin-2-yl)-2-methoxy-4-methylphenyl]ethyl}carbamate(20 mg, 0.045 mmol), 4.0 M HCl in 1,4-dioxane (0.80 mL) was added andthe mixture was stirred for 15 minutes. The solvents were evaporated togive the intermediate. To the residue was added 1-butanol (1.2 mL, 13mmol), DIPEA (40 μL, 0.23 mmol) and6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (16 mg, 0.068 mmol, fromExample 176, Step 4) and the reaction mixture was heated at 120° C. for1 hour. The reaction mixture was cooled to room temperature and 4.0 MHCl in 1,4-dioxane (0.80 mL) was added. The mixture was stirred for 30minutes. Purification by preparative LC/MS (pH 2) gave the desiredcompound (8.2 mg, 32%). LCMS calculated for C₂₂H₂₈ClN₆O₃ (M+H)⁺:m/z=459.2. found: 459.2. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.92 (1H, br s),8.17 (2H, m), 7.60 (1H, s), 5.89 (1H, br s), 5.23 (1H, m), 4.63 (1H, m),4.12 (2H, m), 3.95 (3H, m), 3.62 (1H, m), 3.20 (1H, m), 2.45 (3H, s),1.43 (3H, m), 1.04 (6H, m).

Example 192 Diastereoisomers of4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one

Step 1. Methyl(2E)-3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)acrylate

Into a sealed tube was placed a suspension oftert-butyl[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]carbamate[from Example 113, step 1, peak 2] (1.0 g, 2.6 mmol) in DMF (15 mL) thatwas degassed with nitrogen and treated with methyl acrylate (0.83 mL,9.2 mmol), triphenylphosphine (97 mg, 0.37 mmol), and palladium acetate(59 mg, 0.26 mmol). Lastly, triethylamine (1.1 mL, 7.9 mmol) was addedand the reaction mixture was heated at 130° C. for 16 hours. Aftercooling to room temperature, the mixture was filtered over Celite andthe Celite was washed with EtOAc (100 mL). The EtOAc was washed withwater, brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to a crude foam. The crude material was dissolved in 2:1hexane/dichloromethane and purified by flash column chromatography usingEtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.68g, 68%) as a white foam. LCMS for C₁₄H₁₆ClO₃ (M−NHBoc)⁺: m/z=267.1.Found: 266.9.

Step 2. Methyl3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-4-nitrobutanoate

A solution of methyl(2E)-3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)acrylate(1.5 g, 3.9 mmol) in nitromethane (11 mL) at 0° C. was treated with1,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.9 mmol) and allowed towarm to room temperature. The reaction mixture was heated at 60° C. for21 h, cooled to room temperature, poured into water (100 ml) andextracted with EtOAc (2×75 mL). The organic layer was separated, washedwith brine solution, dried over anhydrous sodium sulfate, filtered, andconcentrated to give a orange foam. The crude material was dissolved indichloromethane and purified by flash column chromatography using EtOAcin hexanes (0%-30% over 30 min) to give the desired product (0.93 g,53%) as a white foam. LCMS for C₂₀H₂₉ClN₂O₇Na (M+Na)⁺: m/z=467.2. Found:467.1.

Step 3. Diastereoisomers of tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate

A solution of methyl3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)-4-nitrobutanoate(0.92 g, 2.1 mmol) in methanol (15 mL) was treated with nickel chloridehexahydrate (0.99 g, 4.1 mmol) and stirred for 5 minutes. The reactionmixture was cooled to 0° C. and treated with sodium tetrahydroborate(0.84 g, 22 mmol) in four portions. The ice bath was removed and thereaction mixture was stirred for 30 min and heated at 60° C. for 4.5hours. The reaction mixture was diluted with saturated sodiumbicarbonate (20 mL) and EtOAc (50 mL) and filtered over Celite. TheCelite was washed with EtOAc and the filtrate was concentrated to givethe desired product as a mixture of diastereoisomers at the lactamcarbon. The mixture of diastereoisomers was separated by chiral HPLC(ChiralPak AD-H column, 20×250 mm, 5 micron particle size, eluting with60% ethanol in hexanes at 9 mL/min, column loading ˜3 mg/injection) togive peak 1 (0.39 g, 49%, retention time: 6.25 min) and peak 2 (0.32 g,40%, retention time: 9.34 min) as white solids.

Step 4. Diastereoisomers of4-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrolidin-2-one

Solutions of the individual diastereoisomers of tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate(75 mg, 0.20 mmol [peak 1 from step 3]; 75 mg, 0.20 mmol [peak 2 fromstep 3]) in separate reaction flasks in methylene chloride (1 mL) wereeach treated individually with trifluoroacetic acid (1 mL) dropwise andstirred for 30 minutes. The reaction mixtures were individuallyconcentrated to residues, diluted with saturated sodium bicarbonate, andextracted several times with dichloromethane to give diastereoisomerfrom peak 1 (60 mg, quantitative) and diastereoisomer from peak 2 (55mg, quantitative) as colorless residues that were used without furtherpurification. Peak 1: LCMS for C₁₄H₁₇ClNO₂ (M−NH₂)⁺: m/z=266.1. Found:266.1. Peak 2: LCMS for C₁₄H₂₀ClN₂O₂ (M+H)⁺: m/z=283.1. Found: 283.1.

Step 5. Diastereoisomers of4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one

Solutions of4-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]pyrrolidin-2-one(43 mg, 0.15 mmol [peak 1 from step 4]; 43 mg, 0.15 mmol [peak 2 fromstep 4]) in separate reaction flasks in 1-butanol (2.4 mL) were eachtreated individually with6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (54 mg, 0.23 mmol, fromExample 176, Step 4), and DIPEA (80 mL, 0.46 mmol) and heated at 105° C.for 20 hours. The reaction mixtures were individually concentrated onthe rotary evaporator at 40° C. to remove 1-butanol to give theTHP-containing intermediates. These intermediates were diluted withmethanol (2 mL) and 6.0 M HCl in water (0.25 mL, 1.5 mmol) and stirredfor 30 min to remove the THP protecting groups. The reaction mixtureswere individually diluted with methanol and purified by preparative LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.1% trifluoroacetic acid, at flow rate of 60 mL/min). The LCMSfractions were concentrated to remove acetonitrile, treated with solidsodium bicarbonate, and extracted into EtOAc. The EtOAc was concentratedand the residues were reconcentrated from EtOAc/heptane to givediastereoisomer from peak 1 (43 mg, 70%) and diastereoisomer from peak 2(42 mg, 69%) as white solids. Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 12.94(br s, 1H), 8.25-8.16 (m, 1H), 8.15-8.08 (m, 1H), 7.88 (s, 1H), 7.52 (brs, 1H), 5.86-5.50 (m, 1H), 4.37-4.22 (m, 1H), 3.88 (s, 3H), 3.61 (dd,J=10.1, 10.1 Hz, 1H), 3.26-3.17 (m, 1H), 2.59 (dd, J=17.3, 11.5 Hz, 1H),2.36 (dd, J=17.2, 8.5 Hz, 1H), 2.22 (s, 3H), 1.43 (d, J=6.9 Hz, 3H).LCMS for C₁₉H₂₂ClN₆O₂ (M+H)⁺: m/z=401.1. Found: 401.2. Peak 2: ¹H NMR(400 MHz, DMSO-d₆) δ 12.94 (br s, 1H), 8.26-8.16 (m, 1H), 8.13-8.04 (m,1H), 7.88 (s, 1H), 7.53 (br s, 1H), 5.81-5.59 (m, 1H), 4.38-4.23 (m,1H), 3.88 (s, 3H), 3.66 (dd, J=10.1, 10.1 Hz, 1H), 3.31-3.24 (m, 1H),2.59-2.52 (m, 1H), 2.29 (dd, J=17.4, 8.4 Hz, 1H), 2.21 (s, 3H), 1.44 (d,J=6.9 Hz, 3H). LCMS for C₁₉H₂₂ClN₆O₂ (M+H)⁺: m/z=401.1. Found: 401.1.

Example 193 Diastereoisomers of4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methylpyrrolidin-2-one

Step 1. Diastereoisomers of tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate

Solutions of the individual diastereoisomers of tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate(0.31 g, 0.80 mmol [peak 1 from Examples 192, step 3]; 0.31 g, 0.80 mmol[peak 2 from Examples 192, step 3]) in DMF (4 mL) at 0° C. were eachtreated individually with sodium hydride dispersed in mineral oil (80mg, 2.0 mmol). The ice bath was removed and the reaction mixtures werestirred for 30 min and heated at 60° C. for 30 minutes. The reactionmixtures were cooled down to 0° C., treated with methyl iodide (0.060mL, 0.96 mmol) in DMF (2 mL, 26 mmol), and stirred at room temperaturefor 16 hours. The reaction mixtures were cooled to 0° C., quenched withsaturated ammonium chloride, and extracted with EtOAc. The organicextract was concentrated to give a crude oil which was purified bypreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of60 mL/min) to give diastereoisomer from peak 1 (28 mg, 9%, retentiontime: 2.52 min) and diastereoisomer from peak 2 (56 mg, 18%, retentiontime: 2.51 min). Peak 1: LCMS for C₂₀H₂₉ClN₂O₄Na (M+Na)⁺: m/z=419.2.Found: 419.1. Peak 2: LCMS for C₂₀H₂₉ClN₂O₄Na (M+Na)⁺: m/z=419.2. Found:419.1.

Step 2. Diastereoisomers of4-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-1-methylpyrrolidin-2-onetrifluoroacetate

Solutions of the individual diastereoisomers of tert-butyl{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate(28 mg, 0.070 mmol [peak 1 from step 1]; 56 mg, 0.14 mmol [peak 2 fromstep 1]) in separate reaction flasks in methylene chloride (1 mL) wereeach treated individually with trifluoroacetic acid (1 mL) dropwise andstirred for 30 minutes. The reaction mixtures were individuallyconcentrated to give diastereoisomer from peak 1 (38 mg, quantitative)and diastereoisomer from peak 2 (65 mg, quantitative) as residues thatwere used without further purification. Peak 1: LCMS for C₁₅H₁₉ClNO₂(M−NH₂)⁺: m/z=280.1. Found: 280.1. Peak 2: LCMS for C₁₅H₂₂ClN₂O₂ (M+H)⁺:m/z=297.1. Found: 297.1.

Step 3. Diastereoisomers of4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methylpyrrolidin-2-one

The desired diastereoisomers were prepared according to the procedure ofExamples 192, step 5, using the diastereoisomers of4-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-1-methylpyrrolidin-2-onetrifluoroacetate as the starting materials in 48% yield (peak 1) and 67%yield (peak 2). Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (br s, 1H),8.31-7.96 (m, 3H), 7.51 (br s, 1H), 5.89-5.52 (m, 1H), 4.31-4.10 (m,1H), 3.86 (s, 3H), 3.71 (dd, J=10.1, 10.1 Hz, 1H), 2.79 (s, 3H),2.75-2.65 (m, 1H), 2.46-2.38 (m, 1H), 2.16 (s, 3H), 1.43 (d, J=6.4 Hz,3H). LCMS for C₂₀H₂₄ClN₆O₂ (M+H)⁺: m/z=415.2. Found: 415.2. Peak 2: ¹HNMR (400 MHz, DMSO-d₆) δ 12.94 (br s, 1H), 8.29-8.17 (m, 1H), 8.16-8.07(m, 2H), 7.54 (br s, 1H), 5.91-5.47 (m, 1H), 4.32-4.10 (m, 1H), 3.87 (s,3H), 3.76 (dd, J=10.1, 10.1 Hz, 1H), 3.44-3.36 (m, 1H), 2.79 (s, 3H),2.68 (dd, J=17.4, 11.7 Hz, 1H), 2.36 (dd, J=17.4, 7.6 Hz, 1H), 2.16 (s,3H), 1.44 (d, J=6.9 Hz, 3H). LCMS for C₂₀H₂₄ClN₆O₂ (M+H)⁺: m/z=415.2.Found: 415.2.

Example 194N-{1-[4,5-Dichloro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

Step 1. 1-(4,5-Dichloro-2-hydroxyphenyl)ethanone

A solution of 3,4-dichlorophenol [AK Scientific] (30 g, 18 mmol) inacetyl chloride (19 mL, 270 mmol) was stirred at 60° C. for 2 hours. Thereaction mixture was cooled to 20° C., treated with aluminum trichloride(37 g, 280 mmol) portionwise, and heated at 180° C. for 30 minutes. Thereaction mixture was cooled to 20° C. and the solution hardened into asolid block that was not easy to break apart. This material was cooledto 0° C. and quenched slowly with 1 M HCl in portions. The solid blockof material slowly broke apart with enough HCl and this heterogenousmixture was stirred at 20° C. overnight to ensure uniformity. The solidwas filtered, washed with copious amounts of water, and dried undervacuum to give the desired product (38 g, quantitative) as a tan solid.

Step 2. 1-(4,5-Dichloro-2-hydroxy-3-iodophenyl)ethanone

A solution of 1-(4,5-dichloro-2-hydroxyphenyl)ethanone (12 g, 59 mmol)in acetic acid (70 mL) was treated with N-iodosuccinimide (16 g, 71mmol) and stirred at 90° C. for 18 hours. The reaction mixture wastreated with additional N-iodosuccinimide (8 g, 36 mmol) and stirred at90° C. for 4 hours. The reaction mixture was concentrated, diluted withEtOAc, and quenched with saturated sodium bicarbonate until the bubblingstopped. The organic layer was separated and the aqueous phase wasre-extracted with EtOAc. The combined organic layers were dried andconcentrated to give a brown solid. This material was recrystallizedfrom methanol to give desired product (9.0 g, 46%) as a tan solid. LCMSfor C₈H₆Cl₂IO₂ (M+H)⁺: m/z=330.9, 332.9. Found: 330.8, 332.9.

Step 3. 1-(4,5-Dichloro-3-iodo-2-methoxyphenyl)ethanone

A solution of 1-(4,5-dichloro-2-hydroxy-3-iodophenyl)ethanone (16 g, 47mmol) and potassium carbonate (17 g, 120 mmol) in DMF (40 mL) wastreated with methyl iodide (6.4 mL, 100 mmol) and stirred at 60° C. for1 hour. The reaction mixture was diluted with water and extracted withEtOAc (twice). The combined organic layers were dried with magnesiumsulfate, filtered, and concentrated to give a crude solid. The crudematerial was purified by flash column chromatography using EtOAc inhexanes (5%-30%) to give the desired product (14 g, 84%) as an orangesolid. LCMS for C₉H₈Cl₂IO₂ (M+H)⁺: m/z=344.9, 346.9. Found: 344.8,346.9.

Step 4. tert-Butyl3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate

Zinc (4.5 g, 69 mmol) was suspended with 1,2-dibromoethane (420 pt, 4.9mmol) in DMF (54 mL). The mixture was heated at 70° C. for 10 min andthen cooled to room temperature. Chlorotrimethylsilane (6204, 4.9 mmol)was added dropwise and stirring was continued for 1 hour. A solution oftert-butyl 3-iodoazetidine-1-carboxylate (17 g, 61 mmol) in DMF (30 mL)was then added and the mixture was heated at 40° C. for 1 h before amixture of 1-(4,5-dichloro-3-iodo-2-methoxyphenyl)ethanone (14 g, 41mmol), tris(dibenzylideneacetone)dipalladium(0) (710 mg, 0.77 mmol) andtri-(2-furyl)phosphine (360 mg, 1.6 mmol) in DMF (120 mL) was addedquickly. The reaction mixture was stirred overnight at room temperature.The reaction mixture was then partitioned between EtOAc and saturatedammonium chloride solution. The organic layer was washed with water,dried with magnesium sulfate, filtered, and concentrated to a cruderesidue that was purified by flash column chromatography using EtOAc inhexanes (0%-25%) to give the desired product (12 g, 77%). LCMS forC₁₇H₂₁Cl₂NO₄Na (M+Na)⁺: m/z=396.1. Found: 396.0.

Step 5. tert-Butyl3-[3-(1-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate

A solution of tert-butyl3-(3-acetyl-5,6-dichloro-2-methoxyphenyl)azetidine-1-carboxylate (1.0 g,2.7 mmol) in 2.0 M ammonia in ethanol (13 mL, 27 mmol) at 0° C. wastreated with titanium tetraisopropoxide (1.6 mL, 5.3 mmol) and stirredat 60° C. overnight. The reaction mixture was treated with sodiumtetrahydroborate (0.15 g, 4.0 mmol) at 0° C. and the solution wasstirred at room temperature for another 1 hour. The reaction mixture wasquenched with 2 M ammonia in water and filtered. The solid was washedwith acetonitrile. The filtrate was concentrated and the residue wasdiluted with dichloromethane, washed with water, dried with magnesiumsulfate, filtered, and concentrated to give the desired product (1.0 g,97%) that was used without further purification. LCMS for C₁₃H₁₄Cl₂NO₃(M−[NH₂]-[t-Bu]+H)⁺: m/z=302.0, 304.0. Found: 301.9, 304.0.

Step 6. tert-Butyl3-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate

A solution of tert-butyl3-[3-(1-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate(4.1 g, 9.7 mmol) and DIPEA (3.4 mL, 20 mmol) in methylene chloride (49mL) at 0° C. was treated with benzyl chloroformate (1.8 mL, 13 mmol) andstirred at 20° C. for 1 hour. The reaction mixture was diluted withdichloromethane (300 mL), washed with saturated sodium bicarbonatesolution, water, and brine, dried with sodium sulfate, filtered andconcentrated to a crude residue that was purified by flash columnchromatography using EtOAc in hexanes (5%-40%) to give the desiredracemic product (4 g, 81%). This racemic material was separated bychiral HPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size,eluting with 30% ethanol in hexanes at 12 mL/min, column loading ˜135mg/injection) to give the desired peak 2 isomer (1.9 g, 38%). Peak 2isomer: LCMS for C₂₅H₃₀Cl₂N₂O₅Na (M+Na)⁺: m/z=531.2. Found: 531.2.

Step 7. Single enantiomer of tert-butyl3-[3-(1-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate

A solution of tert-butyl3-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate[peak 2 isomer from step 6] (0.29 g, 0.57 mmol) in methanol (17 mL) and0.25 M HCl in water (5.7 mL, 1.4 mmol) was degassed with nitrogen,treated with 5% Pt/C (Degussa type) (73 mg, 25 wt %), and stirred undera balloon of hydrogen for 1 hour. The reaction mixture was treated withadditional 5% Pt/C (Degussa type) (100 mg) and stirred under a balloonof hydrogen for an additional 1 hour. The reaction mixture was filteredover Celite and neutralized with saturated sodium bicarbonate solution.The reaction mixture was concentrated to remove the methanol, extractedwith dichloromethane, and concentrated to give the desired product (0.21g, 99%) as a colorless foam that was used without further purification.LCMS for C₁₃H₁₄C₁₂NO₃ (M−[NH₂]−[t-Bu]+H)⁺: m/z=302.0, 304.0. Found:301.9, 304.0.

Step 8.N-[1-(3-Azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine

A solution of tert-butyl3-[3-(1-aminoethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate(0.11 g, 0.28 mmol), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(0.10 g, 0.42 mmol, from Example 176, Step 4), and DIPEA (0.15 mL, 0.85mmol) in 1-butanol (2.8 mL) was heated at 105° C. for 20 hours. Thereaction mixture was concentrated under high vacuum at 40° C. to removethe butanol to give the THP-containing intermediate. This intermediatewas diluted with methanol (1.5 mL) and 6.0 M HCl in water (0.94 mL, 5.7mmol) and stirred at room temperature for 30 minutes. The reactionmixture was concentrated to give the Boc-containing intermediate whichwas dissolved in methylene chloride (1 mL) and trifluoroacetic acid (1mL) and stirred at room temperature for 30 minutes. The reaction mixturewas concentrated to a residue, diluted with methanol, and purified bypreparative LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60mL/min). The LCMS fractions were concentrated to remove acetonitrile,treated with solid sodium bicarbonate, and extracted into EtOAc. Theorganic phase was concentrated and the residues were reconcentrated fromEtOAc/heptane to give the desired product (38 mg, 34%) as a white solid.LCMS for C₁₇H₁₉Cl₂N₆O (M+H)⁺: m/z=393.1. Found: 393.0.

Step 9.N-{1-[4,5-Dichloro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-aminebis(trifluoroacetate)

A solution ofN-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine(18 mg, 0.045 mmol) in methanol (1 mL) was treated with acetone (0.026mL, 0.36 mmol), stirred for 30 mins, treated with sodiumtriacetoxyborohydride (0.028 g, 0.13 mmol), and stirred at roomtemperature for 16 hours. The reaction mixture was purified bypreparative LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60mL/min) to give the desired product (16 mg, 54%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.16 (br s, 1H), 8.65 (br s, 1H), 8.36-8.15 (m, 2H), 7.76(s, 1H), 5.87-5.54 (m, 1H), 4.58-4.41 (m, 2H), 4.40-4.30 (m, 1H),4.28-4.15 (m, 2H), 3.84 (d, J=6.7 Hz, 3H), 3.49-3.28 (m, 1H), 1.49 (d,J=6.9 Hz, 3H), 1.25 (d, J=6.5 Hz, 0.5H), 1.12 (dd, J=6.4, 3.2 Hz, 5.5H).LCMS for C₂₀H₂₅Cl₂N₆O (M+H)⁺: m/z=435.1. Found: 435.1.

Example 195N-{1-[3-(1-Acetylazetidin-3-yl)-4,5-dichloro-2-methoxyphenyl]ethyl}-9H-purin-6-amine

A solution ofN-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine(25 mg, 0.064 mmol, from Example 194, Step 8) in acetonitrile (0.3 mL)was treated with DIPEA (28 μL, 0.16 mmol) followed by acetyl chloride(5.4 μL, 0.076 mmol) and stirred at room temperature for 1 hour. Thereaction mixture was treated with 1N sodium hydroxide (200 μL) andheated briefly with a heat gun. The reaction mixture was diluted withmethanol and purified by preparative LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% ammoniumhydroxide, at flow rate of 60 mL/min) to give the desired product (6.3mg, 23%). ¹N NMR (300 MHz, DMSO-d₆) δ 8.15-8.06 (m, 2H), 7.72 (s, 1H),5.82-5.61 (m, 1H), 4.56-4.45 (m, 1H), 4.43-4.30 (m, 1H), 4.29-4.17 (m,1H), 4.14-4.03 (m, 0.5H), 3.86 (s, 3H), 1.84-1.71 (m, 5H), 1.45 (d,J=6.8 Hz, 3H). LCMS for C₁₉H₂₁Cl₂N₆O₂ (M+H)⁺: m/z=435.1. Found: 435.0.

Example 1962-(3-{2,3-Dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)ethanolbis(trifluoroacetate)

A solution ofN-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine(25 mg, 0.064 mmol, from Example 194, Step 8) in methanol (1 mL) wastreated with sodium cyanoborohydride (10 mg, 0.16 mmol) followed by{[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (36 μL, 0.19 mmol) andstirred at room temperature for 2 hours. The reaction mixture wasdiluted with EtOAc and washed with saturated sodium bicarbonate, water,and brine, dried with sodium sulfate, filtered and concentrated to givethe intermediate silyl ether. This intermediate was dissolved in THF (1mL), cooled at 0° C., treated with 1.0 M tetra-N-butylammonium fluoridein THF (0.64 mL, 0.64 mmol), and stirred at room temperature for 3hours. The reaction mixture was diluted with methanol and purified bypreparative LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60mL/min) to give the desired product (19 mg, 54%). ¹H NMR (300 MHz,DMSO-d₆) δ 9.96 (br s, 1H), 8.50 (br s, 1H), 8.31-8.15 (m, 2H), 7.76 (s,1H), 5.85-5.59 (m, 1H), 4.64-4.17 (m, 7H), 3.88-3.77 (m, 3H), 3.76-3.65(m, 0.5H), 3.63-3.54 (m, 1H), 3.52-3.43 (m, 0.5H), 3.32-3.09 (m, 1H),1.48 (d, J=6.9 Hz, 3H). LCMS for C₁₉H₂₃Cl₂N₆O₂ (M+H)⁺: m/z=437.1, 439.1.Found: 437.1, 439.1.

Example 206(3-{2,3-Dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)acetonitrilebis(trifluoroacetate)

A solution ofN-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine(20 mg, 0.051 mmol, from Example 194, Step 8) in acetonitrile (1 mL) wastreated with DIPEA (22 μL, 0.13 mmol), cooled to 0° C., treated withbromoacetonitrile (4.3 μL, 0.061 mmol), and stirred at 0° C. for 30minutes. The reaction mixture was purified by preparative LCMS (XBridgeC18 Column, eluting with a gradient of acetonitrile in water with 0.1%trifluoroacetic acid, at flow rate of 60 mL/min) to give the desiredproduct (13 mg, 47%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.95 (br s, 1H),8.48-8.22 (m, 2H), 7.71 (s, 1H), 5.88-5.55 (m, 1H), 4.30 (br s, 2H),4.13 (s, 1H), 4.01-3.84 (m, 2H), 3.80 (s, 3H), 1.50 (d, J=6.9 Hz, 3H).LCMS for C₁₉H₂₀Cl₂N₇O (M+H)⁺: m/z=432.1, 434.1. Found: 432.1, 434.1.

Example 207N-(1-{4,5-Dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-aminebis(trifluoroacetate)

Step 1. Benzyl[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]carbamate

A solution of tert-butyl3-[3-(1-{[(benzyloxy)carbonyl]amino}ethyl)-5,6-dichloro-2-methoxyphenyl]azetidine-1-carboxylate(200 mg, 0.39 mmol, from Example 194, Step 6) in methylene chloride (10mL) was treated with trifluoroacetic acid (5 mL) and stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated togive a residue that was dissolved in methanol (˜20 mL) and treated withsaturated sodium bicarbonate solution (pH˜8). The methanol was thenremoved in vacuo to give an aqueous suspension that was diluted withEtOAc. The organic layer was separated and washed with water and brine,dried over anhydrous sodium sulfate, filtered, and concentrated to givethe desired product (180 mg, 98%) that was used without furtherpurification. LCMS for C₂₀H₂₃Cl₂N₂O₃ (M+H)⁺: m/z=409.1, 411.1. Found:409.1, 411.1.

Step 2.Benzyl(1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)carbamate

A solution of benzyl[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]carbamate (170mg, 0.43 mmol) in THF (5.8 mL) was treated with triethylamine (110 μL,0.82 mmol), cooled to 0° C., treated with 2,2,2-trifluoroethyltrifluoromethanesulfonate (150 mg, 0.64 mmol) and stirred at roomtemperature for 30 minutes. The reaction mixture was diluted with EtOAcand washed with saturated sodium bicarbonate, water, and brine, driedwith sodium sulfate, filtered and concentrated to give the desiredproduct (190 mg, 92%) that was used without further purification. LCMSfor C₂₂H₂₄Cl₂F₃N₂O₃ (M+H)⁺: m/z=491.1, 493.1. Found: 491.1, 493.1.

Step 3.1-{4,5-Dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethanaminedihydrochloride

A solution of benzyl(1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)carbamate(190 mg, 0.39 mmol) in methanol (11 mL) was treated with 0.25 M HCl inwater (3.9 mL, 0.98 mmol), degassed with nitrogen for 5 minutes, treatedwith 5% Pt/C (Degussa type) (96 mg, 50 wt %), and stirred under aballoon of hydrogen for 1 hour. The reaction mixture was filtered over aPTFE disposable filter. The filtrate was concentrated to give thedesired product (180 mg, 99%) that was used without furtherpurification. LCMS for C₁₄H₁₈Cl₂F₃N₂O (M+H)⁺: m/z=357.1, 359.1. Found:357.0, 359.0.

Step 4.N-(1-{4,5-Dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-aminebis(trifluoroacetate)

The desired compound was prepared according to the procedure of Example194, step 8, using1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethanaminedihydrochloride as the starting material in 42% yield. ¹H NMR (300 MHz,DMSO-d₆) δ 8.91-8.72 (m, 1H), 8.55-8.16 (m, 2H), 7.69 (s, 1H), 6.00-5.50(m, 1H), 4.51-4.18 (m, 3H), 4.13-3.50 (m, 7H), 1.50 (d, J=6.9 Hz, 3H).LCMS for C₁₉H₂₀Cl₂F₃N₆O (M+H)⁺: m/z=475.1, 477.1. Found: 475.0, 477.0.

Example 210N-(1-{4,5-Dichloro-3-[1-(2,2-difluoroethyl)azetidin-3-yl]-2-methoxyphenyl}ethyl)-9H-purin-6-aminebis(trifluoroacetate)

A solution ofN-[1-(3-azetidin-3-yl-4,5-dichloro-2-methoxyphenyl)ethyl]-9H-purin-6-amine(15 mg, 0.038 mmol, from Example 194, Step 8) in DMF (1 mL) was treatedwith triethylamine (13 μL, 0.095 mmol), cooled to 0° C., treated with2,2-difluoroethyl trifluoromethanesulfonate (12 mg, 0.058 mmol) andstirred at 0° C. for 20 minutes. The reaction mixture was purified bypreparative LCMS (XBridge C18 Column, eluting with a gradient ofacetonitrile in water with 0.1% trifluoroacetic acid, at flow rate of 60mL/min) to give the desired product (12 mg, 46%). ¹H NMR (300 MHz,DMSO-d₆) δ 8.61 (br s, 1H), 8.40-8.11 (m, 2H), 7.76 (s, 1H), 5.89-5.55(m, 1H), 4.66-4.33 (m, 7H), 3.90-3.65 (m, 4H), 1.49 (d, J=6.1 Hz, 3H).LCMS for C₁₉H₂₁Cl₂F₂N₆O (M+H)⁺: m/z=457.1, 459.1. Found: 457.1, 459.1.

Example 2115-{3-Cyano-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

Step 1. 1-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone

The desired compound was prepared according to the procedure of Example172, Step 3, using ethyl iodide as the starting material in 90% yield.LCMS for C₁₀H₁₀ClFIO₂ (M+H)⁺: m/z=342.9, 344.9. Found: 342.9, 344.8.

Step 2. 1-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanamine

The desired compound was prepared according to the procedure of Example179, step 2, using 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanoneas the starting material in 22% yield. LCMS for C₁₀H₁₀ClFIO (M−[NH₂])⁺:m/z=326.9. Found: 327.0.

Step 3. Enantiomer oftert-butyl[1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl]carbamate

The desired racemic compound was prepared according to the procedure ofExample 179, step 3, using1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanamine as the startingmaterial in 80% yield. This racemic material was separated by chiralHPLC (Chiralcel AD-H column, 20×250 mm, 5 micron particle size, elutingwith 30% ethanol in hexanes at 12 mL/min, column loading ˜30mg/injection) to give the desired peak 2 isomer. LCMS for C₁₀H₁₀ClFIO(M−[NHBoc])⁺: m/z=326.9. Found: 326.9.

Step 4,N-[1-(5-Chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

A solution oftert-butyl[1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl]carbamate(1.0 g, 2.3 mmol) in methylene chloride (48 mL) was treated withtrifluoroacetic acid (24 mL) and stirred at room temperature for 0.5hour. The reaction mixture was concentrated and the residue wasre-evaporated from methanol/toluene (2×50 mL) in order to remove allresidual TFA to give the desired amine intermediate. A solution of theamine intermediate in ethanol (20 mL) was treated with DIPEA (1.2 mL,6.8 mmol) followed by 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine(0.81 g, 3.4 mmol, from Example 176, Step 4) and heated at 80° C.overnight. The reaction mixture was diluted with saturated sodiumbicarbonate and diluted with EtOAc. The organic layer was separated andwashed with water and brine, dried with sodium sulfate, filtered andconcentrated to a crude residue which was purified by flash columnchromatography using EtOAc in hexanes (0%-65%) to give the desiredproduct (1.2 g, 94%). LCMS for C₂₀H₂₃ClFIN₅O₂ (M+H)⁺: m/z=546.1. Found:546.0.

Step 5.5-[3-Chloro-6-ethoxy-2-fluoro-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]pyridine-2-carbonitrile

A solution ofN-[1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine(170 mg, 0.31 mmol),5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile(86 mg, 0.37 mmol, Frontier Scientific, Cat. No. C1628), sodiumcarbonate (66 mg, 0.62 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium-(H), complexwith dichloromethane (1:1) (31 mg, 0.037 mmol) in acetonitrile (1.5 mL)and water (0.4 mL) was degassed with nitrogen for 10 min and stirred at95° C. for 2 hours. The reaction mixture was diluted with EtOAc, washedwith saturated sodium bicarbonate, water, and brine, dried over sodiumsulfate, filtered and concentrated to a crude residue which was purifiedby flash column chromatography using EtOAc in hexanes (25%-100%) to givethe desired product (81 mg, 50%). LCMS for C₂₆H₂₆ClFN₇O₂ (M+H)⁺:m/z=522.2. Found: 522.2.

Step 6.5-{3-Chloro-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridine-2-carboxylicacid

A solution of5-[3-chloro-6-ethoxy-2-fluoro-5-(1-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]amino}ethyl)phenyl]pyridine-2-carbonitrile(0.070 g, 0.13 mmol) in ethanol (1.2 mL) was treated with 3 M sodiumhydroxide in water (0.6 mL, 2 mmol) and stirred at 90° C. for 4 h in asealed tube. The reaction mixture was cooled to 0° C., quenched with 12M HCl in water (0.1 mL, 2 mmol), and stirred at 20° C. for 30 minutes.The reaction mixture was treated with additional 12 M HCl in water (0.2mL, 2 mmol) and stirred at 20° C. for 15 minutes. The reaction mixturewas concentrated to give the desired product (61 mg, quantitative) whichwas used without further purification. LCMS for C₂₁H₁₉ClFN₆O₃ (M+H)₊:m/z=457.1. Found: 457.1.

Step 7.5-{3-Chloro-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide

A solution of5-{3-chloro-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridine-2-carboxylicacid (61 mg, 0.13 mmol) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(0.11 g, 0.26 mmol) in DMF (1.4 mL) was treated with 2.0 M dimethylaminein THF (0.26 mL, 0.52 mmol) followed by triethylamine (0.072 mL, 0.52mmol) and stirred at 20° C. for 3 hours. The reaction mixture wasdiluted with EtOAc and washed with water and brine. The organic layerwas separated, dried with magnesium sulfate, filtered, and concentratedto give a crude oil. The crude material was purified by flash columnchromatography using EtOAc in hexanes (0%-70%) to give the desiredproduct (4.7 mg, 7%). LCMS for C₂₃H₂₄ClFN₇O₂ (M+H)⁺: m/z=484.2. Found:484.1.

Step 8.5-{3-Cyano-6-ethoxy-2-fluoro-5-[7-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamidebis(trifluoroacetate)

N,N-Dimethylacetamide (10 mL) was degassed with nitrogen for 10 minutes,then 27 uL of concentrated sulfuric acid was added (to generate a 50 mMsolution), and then bubbled again with nitrogen for 10 minutes.Transferred 2.0 mL of this 50 mM sulfuric acid/DMA solution to amicrowave vial and degassed again with nitrogen. Palladium acetate (23mg, 0.10 mmol) was added, followed bydicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (96 mg, 0.20mmol). The vial was crimp-capped and the mixture was again degassed withnitrogen bubbling for 10 minutes, and then heated at 80° C. for 30 minto give a homogeneous brown solution. This catalyst solution was usedimmediately.

A solution of5-{3-Chloro-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide(20 mg, 0.041 mmol), zinc (1.2 mg, 0.0179 mmol), and zinc cyanide (5.3mg, 0.045 mmol) in N,N-dimethylacetamide (0.5 mL, 5.4 mmol) in amicrowave tube was degassed by bubbling nitrogen through the solutionfor 10 min. The above palladium catalyst solution (150 uL) was added andthe resulting mixture degassed again briefly with nitrogen and heated at110° C. for 1 hour. The reaction mixture was purified by preparativeLCMS (XBridge C18 Column, eluting with a gradient of acetonitrile inwater with 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to givethe desired product (20 mg, 83%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.85-8.79(m, 1H), 8.77 (dd, J=2.2, 0.8 Hz, 1H), 8.37 (s, 2H), 8.10 (d, J=7.4 Hz,1H), 8.02 (dd, J=8.0, 2.2 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 5.94-5.59 (m,1H), 3.91-3.73 (m, 1H), 3.66-3.44 (m, 1H), 3.03 (s, 3H), 2.96 (s, 3H),1.56 (d, J=6.9 Hz, 3H), 1.23 (s, 1H), 1.02 (t, J=6.9 Hz, 3H). LCMS forC₂₄H₂₄FN₈O₂ (M+H)⁺: m/z=475.2. Found: 475.2.

Example 2124-Ethoxy-2-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]-5-[1-(9H-purin-6-ylamino)ethyl]benzonitrilebis(trifluoroacetate)

Step 1.1-{5-Chloro-4-fluoro-2-hydroxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone

The desired compound was prepared according to the procedure of Example127, step A, using 1-(5-chloro-4-fluoro-2-hydroxy-3-iodophenyl)ethanone(See, Example 172, Step 2) and3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(PepTech Corp., Cat. No. BE358) as the starting materials in 87% yield.LCMS for C₁₄H₁₂ClFNO₄S (M+H)⁺: m/z=344.0. Found: 343.9.

Step 2.1-{5-Chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone

A solution of1-{5-chloro-4-fluoro-2-hydroxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanone(1.3 g, 3.6 mmol) in THF (32 mL) was treated with ethanol (0.28 mL, 4.73mmol) and triphenylphosphine (1.3 g, 5.1 mmol). The reaction mixture wascooled to 0° C., treated with diisopropyl azodicarboxylate (1.1 mL, 5.5mmol) dropwise, and stirred at 20° C. for 1 hour. The reaction mixturewas concentrated to remove most of the THF, diluted with EtOAc, washedwith saturated sodium bicarbonate, water, brine, dried over sodiumsulfate, filtered and concentrated to a crude residue which was purifiedby flash column chromatography using EtOAc in hexanes (15%-65%) to givethe desired product (1.2 g, 87%). LCMS for C₁₆H₁₆ClFNO₄S (M+H)⁺:m/z=372.0. Found: 372.1.

Step 3.1-{5-Chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanamine

The desired compound was prepared according to the procedure of Example194, step 5, using1-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanoneas the starting material in 92% yield. LCMS for C₁₆H₁₆ClFNO₃S(M−[NH₂])⁺: m/z=356.1. Found: 356.0.

Step 4. Enantiomer of tert-butyl(1-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate

The desired racemic compound was prepared according to the procedure ofExample 179, step 3, using1-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanamineas the starting material. This racemic material was separated by chiralHPLC (ChiralPak AD-H column, 20×250 mm, 5 micron particle size, elutingwith 10% ethanol in hexanes at 12 mL/min) to give the desired peak 1isomer. LCMS for C₂₁H₂₇ClFN₂O₅S (M+H)⁺: m/z=473.1. Found: 473.2.

Step 5.1-{5-Chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanaminedihydrochloride

The desired compound was prepared according to the procedure of Example179, step 5, using tert-butyl(1-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamateas the starting material in quantitative yield. LCMS for C₁₆H₁₉ClFN₂O₃S(M+H)⁺: m/z=373.1. Found: 373.1.

Step 6.N-(1-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amine

The desired compound was prepared according to the procedure of Example194, step 8, using1-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethanaminedihydrochloride as the starting material in 60% yield. LCMS forC₂₁H₂₁ClFN₆O₃S (M+H)⁺: m/z=491.1. Found: 491.1.

Step 7.4-Ethoxy-2-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]-5-[7-(9H-purin-6-ylamino)ethyl]benzonitrilebis(trifluoroacetate)

The desired racemic compound was prepared according to the procedure ofExample 211, step 8, usingN-(1-{5-chloro-2-ethoxy-4-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amineas the starting material in 82% yield. ¹H NMR (300 MHz, DMSO-d₆) δ 9.17(d, J=2.2 Hz, 1H), 9.09-9.05 (m, 1H), 8.82-8.67 (m, 1H), 8.57-8.52 (m,1H), 8.38-8.31 (m, 2H), 8.17 (d, J=7.5 Hz, 1H), 5.92-5.70 (m, 1H),3.97-3.84 (m, 1H), 3.54-3.44 (m, 1H), 3.40 (s, 3H), 1.58 (d, J=6.9 Hz,3H), 1.04 (t, J=6.9 Hz, 3H). LCMS for C₂₂H₂₁FN₇O₃S (M+H)⁺: m/z=482.1.Found: 482.2.

Example 2136-Chloro-3-ethoxy-2-(1-ethylazetidin-3-yl)-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrilebis(trifluoroacetate)

Step 1. 4-Acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile

A solution of 1-(5-chloro-2-ethoxy-4-fluoro-3-iodophenyl)ethanone (1.0g, 2.9 mmol, from Example 211, Step 1) and potassium cyanide (0.29 g,4.4 mmol) in DMF (11 mL) was stirred at 40° C. for 3 hours. The reactionmixture was diluted with water (100 mL) and extracted with EtOAc (2×75mL). The combined organic layers were washed with brine, dried oversodium sulfate, filtered, and concentrated to a crude orange oil. Thecrude material was dissolved in 1:1 hexane/dichloromethane and purifiedby flash column chromatography using EtOAc in hexanes (0%-30% over 30min) to give the desired product (0.79 g, 77%). LCMS for C₁₁H₁₀ClINO₂(M+H)⁺: m/z=349.9. Found: 349.9.

Step 2. tert-Butyl3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate

The desired compound was prepared according to the procedure of Example165, step 1, using 4-acetyl-6-chloro-3-ethoxy-2-iodobenzonitrile as thestarting material in 82% yield. LCMS for C₁₉H₂₃ClN₂O₄Na (M+Na)⁺:m/z=401.1. Found: 401.0.

Step 3. tert-Butyl3-[3-(1-aminoethyl)-5-chloro-6-cyano-2-ethoxyphenyl]azetidine-1-carboxylate

The desired compound was prepared according to the procedure of Example179, step 2, using tert-butyl3-(3-acetyl-5-chloro-6-cyano-2-ethoxyphenyl)azetidine-1-carboxylate asthe starting material in quantitative yield. LCMS for C₁₉H₂₆ClN₃O₃Na(M+Na)⁺: m/z=402.2. Found: 402.1.

Step 4.2-Azetidin-3-yl-6-chloro-3-ethoxy-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile

The desired compound was prepared according to the procedure of Example194, step 8, using tert-butyl3-[3-(1-aminoethyl)-5-chloro-6-cyano-2-ethoxyphenyl]azetidine-1-carboxylateas the starting material in 90% yield. LCMS for C₁₉H₂₁ClN₇O (M+H)⁺:m/z=398.1. Found: 398.1.

Step 5.6-Chloro-3-ethoxy-2-(1-ethylazetidin-3-yl)-4-[7-(9H-purin-6-ylamino)ethyl]benzonitrilebis(trifluoroacetate)

A solution of2-azetidin-3-yl-6-chloro-3-ethoxy-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile(45 mg, 0.11 mmol) in methanol (1.5 mL) was treated with sodiumcyanoborohydride (0.022 g, 0.35 mmol) followed by acetaldehyde (0.079mL, 1.4 mmol) and stirred at room temperature for 16 hours. The reactionmixture was diluted with methanol and purified by preparative LCMS(XBridge C18 Column, eluting with a gradient of acetonitrile in waterwith 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) to give thedesired product (27 mg, 40%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (br s,1H), 8.50 (br s, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.79 (s, 1H),5.80-5.61 (m, 1H), 4.69-4.47 (m, 3H), 4.42-4.31 (m, 1H), 4.30-4.15 (m,2H), 3.95-3.84 (m, 1H), 3.21-3.07 (m, 1H), 1.49 (d, J=6.9 Hz, 3H), 1.43(t, J=6.9 Hz, 3H), 1.23 (s, 1H), 1.08 (t, J=7.2 Hz, 3H). LCMS forC₂₁H₂₅ClN₇O (M+H)⁺: m/z=426.2. Found: 426.2.

Example 2146-Chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrilebis(trifluoroacetate)

The desired racemic compound was prepared according to the procedure ofExample 213, step 5, using acetone as the starting material in 37%yield. This racemic material was separated by chiral HPLC (ChiralPakAD-H column, 20×250 mm, 5 micron particle size, eluting with 30% ethanolin hexanes at 12 mL/min) to give the desired peak 1 isomer (retentiontime: 13.6 min). ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (br s, 1H), 8.50 (brs, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 5.86-5.58 (m, 1H),4.60-4.46 (m, 3H), 4.45-4.37 (m, 1H), 4.35-4.17 (m, 2H), 3.95-3.87 (m,1H), 3.50-3.31 (m, 1H), 1.49 (d, J=6.9 Hz, 3H), 1.44 (t, J=6.9 Hz, 3H),1.24 (d, J=6.4 Hz, 2H), 1.13 (dd, J=6.4, 3.0 Hz, 3H). LCMS forC₂₂H₂₇ClN₇O (M+H)⁺: m/z=440.2. Found: 440.2.

Experimental procedures for further compounds are summarized in Table 10below.

TABLE 10

Ex. No. Name R Salt Proc.^(a) 197 N-(1-{4,5-Dichloro-2- methoxy-3-[1-(tetrahydrofuran-3- yl)azetidin-3-yl]phenyl} ethyl)-9H-purin-6-aminebistrifluoroacetate

2TFA 194 198 N-(1-{4,5-Dichloro-2- methoxy-3-[1-(2,2,2-trifluoro-1-methylethyl) azetidin-3-yl]phenyl} ethyl)-9H-purin-6- aminebistrifluoroacetate

2TFA 194 199 N-{1-[4,5-Dichloro-2- —CH₃ — 194 methoxy-3-(1-methyl-azetidin-3-yl)phenyl] ethyl}-9H-purin-6-amine 200 N-(1-{4,5-Dichloro-2-methoxy-3-[1-(2- methoxyethyl)azetidin- 3-yl]phenyl}ethyl)-9H-purin-6-amine

— 194 201 N-(1-{4,5-Dichloro- 3-[1-(cyclopropyl- methyl)azetidin-3-yl]-2-methoxyphenyl} ethyl)-9H-purin-6-amine

— 194 202 N-(1-{4,5-dichloro-2- methoxy-3-[1- (tetrahydrofuran-3-ylmethyl)azetidin-3- yl]phenyl}ethyl)-9H- purin-6-amine

— 194 203 N-(1-{4,5-Dichloro-2- methoxy-3-[1-(4,4,4-trifluorobutyl)azetidin- 3-yl]phenyl}ethyl)-9H- purin-6-amine

— 194 204 N-(1-{4,5-Dichloro-2- methoxy-3-[1-(1,3- thiazol-4-ylmethyl)azetidin-3-yl]phenyl} ethyl)-9H-purin-6-amine

— 194 205 N-(1-{4,5-Dichloro-2- methoxy-3-[1-(3,3,3-trifluoropropyl)azetidin- 3-yl]phenyl}ethyl)-9H- purin-6-amine

— 194 208 2-(3-{2,3-Dichloro-6- methoxy-5-[1-(9H- purin-6-ylamino)ethyl]phenyl}azetidin-1- yl)propan-1-ol bistrifluoroacetate

2TFA 194 209 N-{1-[4,5-Dichloro- 3-(1-cyclobutylazetidin-3-yl)-2-methoxyphenyl] ethyl}-9H-purin-6-amine bistrifluoroacetate

2TFA 194 ^(a 1)H NMR data (Varian Inova 500 spectrometer, a Mercury 400spectrometer, or a Varian (or Mercury) 300 spectrometer) and LCMS massspectral data (MS) for the compounds above is provided below in Table11.

TABLE 11 ¹H NMR data for compounds in Table 10 Ex. MS No. [M + H]⁺Solvent MHz ¹H NMR Spectra 197 463.0, 465.0 DMSO- 300 δ 10.44 (br s,1H), 9.93 (br s, 0.5H), 8.78-8.65 (m, 1H), d₆ 8.37-8.25 (m, 2H), 7.75(s, 1H), 5.97-5.53 (m, 1H), 4.70-4.57 (m, 2H), 4.43-4.20 (m, 3H),4.12-4.01 (m, 0.5H), 3.94-3.86 (m, 1.5H), 3.83 (s, 3H), 3.69-3.53 (m,2H), 2.24-2.05 (m, 1H), 1.98-1.81 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H). 198489.0, DMSO- 300 δ 8.64 (br s, 1H), 8.34-8.20 (m, 2H), 7.68 (s, 1H),491.0 d₆ 5.83-5.57 (m, 1H), 4.29-4.04 (m, 4H), 3.81 (s, 3H), 3.74-3.38(m, 3H), 1.48 (d, J = 6.9 Hz, 3H), 1.14 (d, J = 6.2 Hz, 3H). 199 407.0,DMSO- 300 δ 8.30-7.94 (m, 3H), 7.62 (s, 1H), 5.97-5.53 (m, 1H), 409.0 d₆3.99-3.81 (m, 3H), 3.79 (s, 3H), 2.95 (dd, J = 8.9, 6.5 Hz, 1H), 2.81(dd, J = 8.8, 6.4 Hz, 1H), 2.15 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H). 200451.0, DMSO- 300 δ 8.16-7.97 (m, 3H), 7.63 (s, 1H), 5.87-5.54 (m, 1H),453.0 d₆ 4.00-3.83 (m, 3H), 3.79 (s, 3H), 3.31-3.26 (m, 4H), 3.21 (s,3H), 3.07-2.94 (m, 1H), 2.94-2.82 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H). 201447.0 DMSO- 300 δ 8.30-7.97 (m, 3H), 7.62 (s, 1H), 5.88-5.53 (m, 1H), d₆4.01-3.84 (m, 3H), 3.80 (s, 3H), 3.00-2.91 (m, 1H), 2.87-2.77 (m, 1H),2.16 (d, J = 6.6 Hz, 2H), 1.44 (d, J = 6.9 Hz, 3H), 0.81-0.63 (m, 1H),0.49-0.25 (m, 2H), 0.09-−0.02 (m, 2H). 202 477.1 DMSO- 300 δ 8.19-8.07(m, 3H), 7.62 (s, 1H), 5.86-5.48 (m, 1H), d₆ 4.04-3.83 (m, 3H), 3.80 (s,3H), 3.77-3.53 (m, 3H), 3.04-2.92 (m, 1H), 2.90-2.77 (m, 1H), 2.35-2.26(m, 2H), 2.24-2.10 (m, 1H), 2.00-1.80 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H).203 503.1 DMSO- 300 δ 8.22-8.03 (m, 3H), 7.63 (s, 1H), 5.91-5.50 (m,1H), d₆ 4.03-3.85 (m, 3H), 3.80 (s, 3H), 3.04-2.90 (m, 1H), 2.90-2.77(m, 1H), 2.40-2.15 (m, 4H), 1.56-1.36 (m, 4H). 204 490.0 DMSO- 300 δ9.03 (d, J = 2.0 Hz, 1H), 8.25-8.03 (m, 3H), 7.63 (s, d₆ 1H), 7.47 (d, J= 1.9 Hz, 1H), 5.97-5.50 (m, 1H), 4.08-3.85 (m, 3H), 3.80 (s, 3H), 3.66(s, 2H), 3.20-3.11 (m, 1H), 3.09-2.97 (m, 1H), 1.44 (d, J = 6.9 Hz, 3H).205 489.0 DMSO- 300 δ 8.25-7.97 (m, 3H), 7.63 (s, 1H), 5.97-5.45 (m,1H), d₆ 4.02-3.84 (m, 3H), 3.80 (s, 3H), 3.01 (dd, J = 8.5, 6.3 Hz, 1H),2.93-2.86 (m, 1H), 2.41-2.18 (m, 2H), 1.44 (d, J = 6.9 Hz, 3H). 208451.0, DMSO- 300 δ 10.01 (br s, 1H), 8.63-8.44 (m, 1H), 8.36-8.14 (m,453.0 d₆ 2H), 7.76 (s, 1H), 5.86-5.60 (m, 1H), 4.59-4.45 (m, 2H),4.43-4.22 (m, 3H), 3.84 (d, J = 3.0 Hz, 3H), 3.70-3.55 (m, 1H),3.50-3.31 (m, 2H), 1.49 (d, J = 6.8 Hz, 3H), 1.28-1.17 (m, 0.5H),1.16-1.02 (m, 2.5H). 209 447.1, DMSO- 300 δ 10.54 (br s, 1H), 9.83 (brs, 0.5H), 8.57 (br s, 1H), 449.1 d₆ 8.39-8.16 (m, 2H), 7.75 (s, 1H),5.71 (m, 1H), 4.60-4.47 (m, 2H), 4.45-4.21 (m, 2H), 4.19-4.06 (m, 2H),3.89-3.80 (m, 3H), 2.19-1.97 (m, 4H), 1.87-1.63 (m, 1H), 1.48 (d, J =6.9 Hz, 3H), 1.23 (s, 1H).

Example A PI3Kδ Scintillation Proximity Assay

Materials:

[γ-³³P]ATP (10 mCi/mL) was purchased from Perkin-Elmer (Waltham, Mass.).Lipid kinase substrate, D-myo-Phosphatidylinositol 4,5-bisphosphate(PtdIns(4,5)P2)D (+)-sn-1,2-di-O-octanoylglyceryl, 3-O-phospho linked(PIP2), CAS 204858-53-7, was purchased from Echelon Biosciences (SaltLake City, Utah). PI3Kδ (p110δ/p85α) was purchased from Millipore(Bedford, Mass.). ATP, MgCl₂, DTT, EDTA, MOPS and CHAPS were purchasedfrom Sigma-Aldrich (St. Louis, Mo.). Wheat Germ Agglutinin (WGA) YSi SPAScintillation Beads was purchased from GE healthcare life sciences(Piscataway, N.J.).

Assay:

The kinase reaction was conducted in polystyrene 384-well matrix whiteplate from Thermo Fisher Scientific in a final volume of 25 μL.Inhibitors were first diluted serially in DMSO and added to the platewells before the addition of other reaction components. The finalconcentration of DMSO in the assay was 0.5%. The PI3K assays werecarried out at room temperature in 20 mM MOPS, pH 6.7, 10 mM MgCl₂, 5 mMDTT and CHAPS 0.03%. Reactions were initiated by the addition of ATP,the final reaction mixture consisted of 20 μM PIP2, 20 μM ATP, 0.2 μCi[γ-³³P] ATP, 4 nM PI3Kδ. Reactions were incubated for 210 minutes andterminated by the addition of 40 μL SPA beads suspended in quenchbuffer: 150 mM potassium phosphate pH 8.0, 20% glycerol. 25 mM EDTA, 400μM ATP. The final concentration of SPA beads is 1.0 mg/mL. After theplate sealing, plates were shaken overnight at room temperature andcentrifuged at 1800 rpm for 10 minutes, the radioactivity of the productwas determined by scintillation counting on Topcount (Perkin-Elmer).IC₅₀ determination was performed by fitting the curve of percent controlactivity versus the log of the inhibitor concentration using theGraphPad Prism 3.0 software. Table 12 shows PI3Kδ scintillationproximity assay data for certain compounds described herein.

TABLE 12 IC₅₀ data for PI3Kδ scintillation proximity assay Example IC₅₀(nM)  1 B  2 A  3 C  4 E  5 A  6 A  7 A  8 A  9 B  10 A  11 A  12 A  13A  14 A  15 A  16 A  17 A  18 D  19 A  20 A  21 A  22 A  23 A  24 A  25A  26 A  27 A  28 A  29 A  30 A  31 A  32 A  33 A  34 A  35 B  36 A  37A  38 C  39 C  40 A  41 A  42 A  43 A  44 A  45 A  46 A  47 C  48 A  49A  50^(a) A/B  51 A  52 A  53 A  54^(a) A/A  55 A  56 A  57 A  58 B  59C  60 A  61 A  62 A  63 A  64 A  65 A  66 A  67 A  68 A  69 A  70 A  71A  72 A  73 A  74^(a) A/A  75^(a) A/A  76 A  77 A  78 A  79 C  80 A  81A  82 A  83 A  84 A  85 D  86^(a) B/C  87 A  88 A  89 B  90 D  91 B  92C  93 B  94 A  95 A  96 A  97 B  98 A  99 D 100 A 101 C 102 C 103 A 104A 105 A 106 A 107 A 108 A 109 A 110 A 111 A 112 A 113 A 114 A 115 A 116A 117 A 118 B 119 C 120 B 121 A 122 D 123 B 124 A 125 B 126 A 127 A 128A 129 A 130 A 131 A 132 A 133 B 134 A 135 A 136 C 137 B 138 B 139 B 140B 141 D 142 B 143 C 144 A 145 A 146 B 147 A 148 B 149 A 150 A 151 A 152A 153 A 154 A 155 A 156 A 157 A 158 A 159 A 160 A 161 A 162 A 163 A 164A 165 A 166 A 167 A 168 A 169 A 170 A 171 A 172 A 173 A 174 A 175 A 176A 177 A 178 A 179 A 180 A 181 A 182 A 183 A 184 A 185 A 186 A 187 A 188A 189 A 190 A 191 A 192^(a) A/A 193^(a) A/A 194 A 195 A 196 A 197 A 198A 199 A 200 A 201 A 202 A 203 A 204 A 205 A 206 A 207 A 208 A 209 A 210A 211 A 212 A 213 A 214 A *“A” = <50 nM; “B” = 50 nM-100 nM; “C” = >100nM to 250 nM; “D” = >250 nM to 500 nM; “E” = >500 nM to 1 μM; and “F”= >1 μM; nt = not tested ^(a)two isomers were isolated in thecorresponding experiments and they were tested respectively

Example B B Cell Proliferation Assay

To acquire B cells, human PBMC are isolated from the peripheral blood ofnormal, drug free donors by standard density gradient centrifugation onFicoll-Hypague (GE Healthcare, Piscataway, N.J.) and incubated withanti-CD19 microbeads (Miltenyi Biotech, Auburn, Calif.). The B cells arethen purified by positive immunosorting using an autoMacs (MiltenyiBiotech) according to the manufacture's instruction.

The purified B cells (2×10⁵/well/200 μL) are cultured in 96-wellultra-low binding plates (Corning, Corning, N.Y.) in RPMI1640, 10% FBSand goat F(ab′)2 anti-human IgM (10 μg/ml) (Invitrogen, Carlsbad,Calif.) in the presence of different amount of test compounds for threedays. [³H]-thymidine (1 μCi/well) (PerkinElmer, Boston, Mass.) in PBS isthen added to the B cell cultures for an additional 12 hours before theincorporated radioactivity is separated by filtration with water throughGF/B filters (Packard Bioscience, Meriden, Conn.) and measured by liquidscintillation counting with a TopCount (Packard Bioscience).

Example C Pfeiffer Cell Proliferation Assay

Pfeiffer cell line (diffuse large B cell lymphoma) was purchased fromATCC (Manassas, Va.) and maintained in the culture medium recommended(RPMI and 10% FBS). To measure the anti-proliferation activity of thecompounds, the Pfeiffer cells were plated with the culture medium (2×10³cells/well/per 200 μl) into 96-well ultra-low binding plates (Corning,Corning, N.Y.), in the presence or absence of a concentration range oftest compounds. After 3-4 days, [³H]-thymidine (1 μCi/well)(PerkinElmer, Boston, Mass.) in PBS was then added to the cell culturefor an additional 12 hours before the incorporated radioactivity wasseparated by filtration with water through GF/B filters (PackardBioscience, Meridenj, Conn.) and measured by liquid scintillationcounting with a TopCount (Packard Bioscience). Table 13 shows Pfeiffercell proliferation data for certain compounds described herein.

TABLE 13 IC₅₀ data for Pfeiffer cell proliferation assay* Example IC₅₀(nM)  1 C  2 A  3 D  5 A  6 A  7 A  8 D  9 B  10 B  11 A  12 A  13 A  14A  15 A  16 A  17 A  18 B  19 A  20 B  21 A  22 A  23 A  24 B  25 A  26A  27 B  28 B  29 B  30 B  31 A  32 A  33 A  34 A  35 D  36 A  37 A  38D  39 D  40 A  41 D  42 B  43 B  44 B  45 B  46 A  47 D  48 A  49 A 50^(a) D/C  51 A  52 A  53 A  60 D  71 A  72 A  73 A  74^(a) A/A 75^(a) A/B  76 A  77 A  78 A  79 B  80 A  81 A  82 A  83 A  84 A 86^(a) D/D  87 A  88 A  89 C  91 D  92 B  93 D  94 A  95 C  96 A  97 B 98 A 100 D 106 A 107 B 109 A 110 B 111 A 112 A 124 A 166 A 170 A 174 A176 A 177 A 178 A 179 A 180 A 187 A 194 A 195 A 196 A 197 A 199 A 200 A201 A 202 A 203 A 204 A 205 A 208 A 212 B 213 A *“A” = <100 nM; “B” =100 nM-500 nM; “C” = >500 nM to 1 μM; “D” = >1 μM ^(a)two isomers wereisolated in the corresponding experiments and they were testedrespectively

Example D Akt Phosphorylation Assay

Ramos cells (B lymphocyte from Burkitts lymphoma) are obtained from ATCC(Manassas, Va.) and maintained in RPMI1640 and 10% FBS. The cells (3×10⁷cells/tube/3 mL in RPMI) are incubated with different amounts of testcompounds for 2 h at 37° C. and then stimulated with goat F(ab′)2anti-human IgM (5 μg/mL) (Invitrogen) for 17 minutes in a 37° C. waterbath. The stimulated cells are spun down at 4° C. with centrifugationand whole cell extracts are prepared using 300 μL lysis buffer (CellSignaling Technology, Danvers, Mass.). The resulting lysates aresonicated and supernatants are collected. The phosphorylation level ofAkt in the supernatants are analyzed by using PathScan phospho-Akt1(Ser473) sandwich ELISA kits (Cell Signaling Technology) according tothe manufacturer's instruction.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patent,patent applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Ar is H

X is CH or N; Y is CH or N; R¹ is selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted by 1, 2, 3, or4 groups independently selected from halo, OH, CN, NR^(1a)R^(2b), C₁₋₆alkoxy, and C₁₋₆ haloalkoxy; each R^(1a) and R^(2b) is independentlyselected from H and C₁₋₆ alkyl; or any R^(1a) and R^(2b) together withthe N atom to which they are attached form a 4-, 5-, 6-, or 7-memberedheterocycloalkyl group, which is optionally substituted with 1, 2, 3, or4 substituents independently selected from C₁₋₆ alkyl; R² is selectedfrom halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, -L-(C₁₋₆ alkyl), -L-(C₁₋₆haloalkyl), and -L-(C₁₋₄ alkylene)_(n)-Cy² and —(C₁₋₄ alkylene)_(n)-Cy²;wherein said C₁₋₆ alkyl in said C₁₋₆ alkyl and -L-(C₁₋₆ alkyl) isoptionally substituted by 1, 2, 3, or 4 independently selected R^(2a)groups; L is O, NR^(B), S, S(O), S(O)₂, C(O), C(O)NR^(B), S(O)NR^(B),S(O)₂NR^(B), NR^(B)C(O), NR^(B)S(O), and NR^(B)S(O)₂; R^(A) and R^(B)are each independently selected from H and C₁₋₆ alkyl; Cy² is selectedfrom C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6membered heteroaryl; each of which is substituted with p independentlyselected R^(2a) groups; wherein p is 0, 1, 2, 3, or 4; each R^(2a) isindependently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,amino sulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, amino carbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino; R³ ishalo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,—(C₁₋₄ alkylene)_(r)-Cy³, OR^(n), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(b), NR^(f)C(O)R^(b), NR^(f)C(O)OR^(b),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NR^(e))NR^(c)R^(d),NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),NR^(f)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), or S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl are each optionally substituted by 1, 2, 3, or 4independently selected R^(3a) groups; Cy³ is selected from C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(3a) groups; provided that one of the followingis true: (1) R³ is —(C₁₋₄ alkylene)_(r)-Cy³; or (2) R² is selected from-L-(C₁₋₄ alkylene)_(n)-Cy² and —(C₁₋₄ alkylene)_(n)-Cy²; or (3) R³ is—(C₁₋₄ alkylene)_(r)-Cy³; and R² is selected from -L-(C₁₋₄alkylene)_(n)-Cy² and —(C₁₋₄ alkylene)_(n)-Cy²; each R^(3a) isindependently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, (5-6 memberedheteroaryl)-C₁₋₄ alkyl, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(b), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, phenyl,5-6 membered heteroaryl, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl,phenyl-C₁₋₄ alkyl, and (5-6 membered heteroaryl)-C₁₋₄ alkyl are eachoptionally substituted by 1, 2, 3, or 4 groups independently selectedfrom OH, NO₂, CN, halo, C₁₋₆ alkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl,C₁₋₄ alkoxy-C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, amino sulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; R⁴ is selected from H, OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,amino sulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino; R⁵ isselected from halo, OH, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₁₋₄haloalkoxy; each R^(a), R^(c), and R^(d) is independently selected fromH, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, 5-6 memberedheteroaryl, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄alkyl, and (5-6 membered heteroaryl)-C₁₋₄ alkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7 memberedheterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, and (5-6 memberedheteroaryl)-C₁₋₄ alkyl are each optionally substituted with 1, 2, 3, 4,or 5 substituents independently selected from OH, NO₂, CN, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl,HO—C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl,C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino; each R^(b) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, 4-7membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl, phenyl-C₁₋₄ alkyl, and (5-6membered heteroaryl)-C₁₋₄ alkyl; each optionally substituted with 1, 2,3, 4, or 5 substituents independently selected from OH, NO₂, CN, halo,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cyano-C₁₋₆alkyl, HO—C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, and di(C₁₋₆alkyl)amino carbonylamino; each R^(e) is independently selected from H,C₁₋₄ alkyl, CN, OH, C₁₋₄ alkoxy, C₁₋₄ alkylsulfonyl, carbamyl, C₁₋₄alkylcarbamyl, di(C₁₋₄ alkyl)carbamyl, and C₁₋₄ alkylcarbonyl; eachR^(f) is independently selected from C₁₋₄ alkylsulfonyl, C₁₋₄alkylcarbonyl and C₁₋₄ alkoxycarbonyl; n is 0 or 1; and r is 0 or
 1. 2.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein Ar is H


3. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁴ is selected from H, halo, CN, C₁₋₆ alkyl, cyano-C₁₋₆alkyl, and C₁₋₆ haloalkyl.
 4. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is C₁₋₃ alkyl. 5.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is methyl.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is C₁₋₆ alkyl, —O—(C₁₋₆ alkyl),—O—(C₁₋₄ alkylene)_(n)-(4-7 membered heterocycloalkyl), or phenyl;wherein said phenyl is optionally substituted by 1, 2, 3, or 4independently selected R^(2a) groups.
 7. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein each R^(2a) isindependently halo.
 8. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R² is methoxy.
 9. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R^(A) is H.10. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R⁵ is Cl, F, methyl or CN.
 11. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein R³ is CN, NO₂,Cy³, C(O)NR^(c)R^(d), NR^(f)C(O)OR^(b), NR^(f)S(O)₂R^(b), andNR^(c)C(O)R^(b).
 12. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R³ is Cy³.
 13. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Cy³ is selectedfrom 4-7 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl;each of which is optionally substituted with 1, 2, 3, or 4 independentlyselected R^(3a) groups.
 14. The compound of claim 1, wherein: Cy³ isselected from phenyl, a piperidine ring, a pyrrolidin-2-one ring, a1,3-oxazolidin-2-one ring, an isoxazole ring, a pyrazole ring, atetrazole ring, a triazole ring, a pyridine ring, a pyrimidine ring, anazetidine ring, a pyrrole ring, a tetrahydrofuran ring, and amorpholin-2-one ring; each of which is optionally substituted with 1, 2,3, or 4 independently selected R^(3a) groups; each R^(a), R^(c), andR^(d) is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₃₋₇ cycloalkyl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, and amino; and each R^(b) is independently selected fromC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl; each of which is optionally substituted with 1, 2, 3,4, or 5 substituents independently selected from OH, CN, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and amino.
 15. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: Ar is H

R¹ is C₁₋₆ alkyl; R^(A) is H; R² is C₁₋₆ alkyl, —O—(C₁₋₆ alkyl),—O—(C₁₋₄ alkylene)_(n)-(4-7 membered heterocycloalkyl), or phenyl;wherein said phenyl is optionally substituted by 1, 2, 3, or 4independently selected R^(2a) groups; Cy² is selected from C₃₋₇cycloalkyl, 4-7 membered heterocycloalkyl, phenyl, and 5-6 memberedheteroaryl; each of which is optionally substituted with 1, 2, 3, or 4independently selected R^(2a) groups; R³ is CN, NO₂, Cy³,C(O)NR^(c)R^(d), NR^(f)C(O)OR^(b), NR^(f)S(O)₂R^(b), andNR^(c)C(O)R^(b); Cy³ is selected from C₃₋₇ cycloalkyl, 4-7 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl; each of which isoptionally substituted with 1, 2, 3, or 4 independently selected R^(3a)groups; R⁴ is selected from C₁₋₆ alkyl, cyano-C₁₋₆ alkyl, and C₁₋₆haloalkyl; and R⁵ is halo; each R^(2a) is independently selected fromOH, NO₂, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino; each R^(3a)is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, OR^(a),C(O)R^(b), C(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), andS(O)₂R^(b); wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 4-7 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 groupsindependently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl,cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄ alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino, and di(C₁₋₆ alkyl)amino; eachR^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy; and each R^(b) isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl,4-7 membered heterocycloalkyl; each of which is optionally substitutedwith 1, 2, 3, 4, or 5 substituents independently selected from OH, CN,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and C₁₋₆ haloalkoxy. 16.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein: Ar is

R¹ is methyl or ethyl; R^(A) is H; R² is selected from C₁₋₆ alkyl,—O—(C₁₋₆ alkyl), —O—(C₁₋₄ alkylene)_(n)-(4-7 membered heterocycloalkyl),and phenyl; wherein said phenyl is optionally substituted by 1, 2, 3, or4 independently selected halo groups; R³ is selected from CN, NO₂, Cy³,C(O)NR^(c)R^(d), NR^(f)C(O)OR^(b), NR^(f)S(O)₂R^(b), andNR^(c)C(O)R^(b); Cy³ is selected from phenyl, a piperidine ring, apyrrolidin-2-one ring, a 1,3-oxazolidin-2-one ring, an isoxazole ring, apyrazole ring, a tetrazole ring, a triazole ring, a pyridine ring, apyrimidine ring, an azetidine ring, a pyrrole ring, a tetrahydrofuranring, and a morpholin-2-one ring; each of which is optionallysubstituted with 1, 2, 3, or 4 independently selected R^(3a) groups; R⁴is selected from H, halo, C₁₋₃ alkyl, CN, cyano-C₁₋₆ alkyl, and C₁₋₆haloalkyl; R⁵ is selected from C₁₋₃ alkyl, halo, and CN; each R^(3a) isindependently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl, (4-7 memberedheterocycloalkyl)-C₁₋₃ alkyl, (5-6 membered heteroaryl)-C₁₋₃ alkyl,OR^(a), C(O)R^(b), C(O)OR^(a), C(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), and S(O)₂R^(b); wherein said C₁₋₆ alkyl, C₃₋₇cycloalkyl, and 4-7 membered heterocycloalkyl are each optionallysubstituted by 1, 2, 3, or 4 groups independently selected from OH, CN,halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyano-C₁₋₆ alkyl, HO—C₁₋₆ alkyl, C₁₋₄alkoxy-C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, amino, C₁₋₆ alkylamino,di(C₁₋₆ alkyl)amino, and C₃₋₇ cycloalkyl; each R^(a), R^(c), and R^(d)is independently selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₇cycloalkyl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl,C₃₋₇ cycloalkyl, and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, 4, or 5 substituents independently selectedfrom OH, CN, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, and amino; each R^(b) is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₇ cycloalkyl, 4-7 membered heterocycloalkyl;each of which is optionally substituted with 1, 2, 3, 4, or 5substituents independently selected from OH, CN, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, and amino; and each R^(f) isindependently selected from C₁₋₄ alkylcarbonyl and C₁₋₄ alkoxycarbonyl.17. The compound of claim 1, having Formula II:

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim1, having Formula IIa:

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 1, selected from:4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile;4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide;N-[1-(4-chloro-3′-fluoro-5-methyl-6-nitrobiphenyl-2-yl)ethyl]-9H-purin-6-amine;4-Chloro-3-(cyanomethyl)-3′-fluoro-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile;1-{4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-one;1-{4-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}pyrrolidin-2-one;3-{4-Chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-1,3-oxazolidin-2-one;N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1H-tetrazol-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}acetamide;Dimethyl{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}imidodicarbonate;N-{1-[4-chloro-3′-fluoro-5-methyl-6-(4H-1,2,4-triazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-yl}-N-(methylsulfonyl)methanesulfonamide;N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;1-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one;4-Chloro-3′,5′-difluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carboxamide;N-(1-{5-chloro-3-[2-(dimethylamino)pyrimidin-5-yl]-2-methoxy-4-methylphenyl}ethyl)-9H-purin-6-amine;1-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}piperidin-4-ol;3′-Chloro-4-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;3′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;1-({3′-Chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}carbonyl)azetidine-3-carbonitrile;N-{1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′-fluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[4-Chloro-3′-fluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-[1-(4-Chloro-3′,5′-difluoro-5-methyl-6-pyridin-4-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;N-{1-[4-Chloro-3′,5′-difluoro-5-methyl-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[5-Chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-Chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;(4-{3-Chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1H-pyrazol-1-yl)acetonitrile;N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3-(3,5-dimethylisoxazol-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-3-(2-methoxypyrimidin-5-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}acetamide;N-[1-(5-chloro-3′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-[1-(5-chloro-3′,5′-difluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carbonitrile;3′-chloro-N-cyclopropyl-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;N-{1-[5-chloro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-3-(5-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;N-[1-(3′,5-dichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-3-(5-chloropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;3,3′-dichloro-6′-methoxy-N,2′-dimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;N-{1-[5-chloro-2-methoxy-6-methyl-4′-(trifluoromethyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-[1-(5-chloro-4′-ethoxy-3′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carbonitrile;{3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}acetonitrile;N-{1-[5-chloro-2-methoxy-4′-(methoxymethyl)-6-methylbiphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-6-methyl-4′-(1H-pyrazol-1-yl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-3′-(methoxymethyl)-6-methylbiphenyl-3-yl]ethyl}-9H-purin-6-amine;N-(1-{5-chloro-2-methoxy-4-methyl-3-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amine;{3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-yl}acetonitrile;N-[1-(3′,5,5′-trichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-4-methyl-3-(6-morpholin-4-ylpyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3-(3-fluoro-2-morpholin-4-ylpyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-[1-(5-chloro-2′,5′-difluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-3-(6-methoxypyridin-3-yl)-4-methylphenyl]ethyl}-9H-purin-6-amine;5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}nicotinonitrile;3-(4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1H-pyrazol-1-yl)-3-(cyanomethyl)cyclobutanecarbonitrile;N-{1-[5-chloro-2-methoxy-4-methyl-3-(5-methylpyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;N-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-{1-[3-(6-aminopyridin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridine-2-carbonitrile;N-{1-[5-chloro-3-(6-isopropoxypyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;3′-chloro-N-ethyl-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;3′-chloro-3-fluoro-6′-methoxy-N,N,2′-trimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;N-{1-[5-chloro-3′-fluoro-2-methoxy-6-methyl-4′-(pyrrolidin-1-ylcarbonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3′-fluoro-2-methoxy-6-methyl-4′-(morpholin-4-ylcarbonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;3′-chloro-3-fluoro-6′-methoxy-N,2′-dimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;1-({3′-chloro-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}carbonyl)piperidin-4-ol;3′-chloro-N-cyclobutyl-3-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;N-{1-[5-chloro-3-(2-fluoropyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-[1-(3′,5-dichloro-5′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-2′-fluoro-2-methoxy-6-methyl-5′-(trifluoromethyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3-(6-fluoro-5-methylpyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-[1-(5-chloro-2-methoxy-6-methyl-4′-morpholin-4-ylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-[1-(3′,5-dichloro-4′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-6-methyl-4′-(trifluoromethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-[1-(5-chloro-3′-ethoxy-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-[1-(4′,5-dichloro-3′-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-4′-fluoro-2-methoxy-6-methyl-3′-(trifluoromethyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;3′-chloro-4-fluoro-6′-methoxy-N,N,2′-trimethyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;N-[1-(5-chloro-4′-fluoro-2,3′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-[1-(5-chloro-2,3′,4′-trimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-[1-(3′,5-dichloro-2,4′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-3-(2-chloropyridin-4-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-[1-(4′,5-dichloro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-3′-(dimethylamino)-2-methoxy-6-methylbiphenyl-3-yl]ethyl}-9H-purin-6-amine;N-[1-(5-chloro-2,4′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-[1-(5-chloro-2,4′-dimethoxy-3′,6-dimethylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-[1-(5-chloro-2,3′-dimethoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{3′-chloro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-yl}acetamide;N-[1-(5-chloro-3′,4′-difluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-3-(5-fluoro-6-methoxypyridin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;3′-chloro-5-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;N-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(morpholin-4-ylcarbonyl)pyridin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)acetamide;5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}nicotinonitrile;N-{1-[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[5′-chloro-6′-methyl-4-(methylsulfonyl)-1,1′:2′,1″-terphenyl-3′-yl]ethyl}-9H-purin-6-amine;N-(1-{4-chloro-6-[2-(dimethylamino)pyrimidin-5-yl]-5-methylbiphenyl-2-yl}ethyl)-9H-purin-6-amine;5′-chloro-N-cyclopropyl-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-carboxamide;N-{1-[6-(2-aminopyrimidin-5-yl)-4-chloro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;5′-chloro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-carbonitrile;N-{1-[4-chloro-6-(2-methoxypyrimidin-5-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{5′-chloro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-yl}acetamide;N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1-methyl-1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1-methyl-1H-pyrazol-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[4-chloro-3′-fluoro-5-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[4-chloro-6-(3,5-dimethylisoxazol-4-yl)-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-[1-(4-chloro-3′,5′-difluoro-5-methyl-6-pyridin-3-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;5′-chloro-3″,5″-difluoro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-carbonitrile;N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-[1-(4-chloro-3′,5′-difluoro-5-methyl-6-pyrimidin-5-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;N-{1-[4-chloro-3′,5′-difluoro-6-(2-methoxypyrimidin-5-yl)-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{5′-chloro-3″,5″-difluoro-6′-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-yl}acetamide;N-{1-[4-chloro-6-(3,5-dimethyl-1H-pyrazol-4-yl)-3′,5′-difluoro-5-methylbiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[5-fluoro-2-methoxy-6-methyl-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-[1-(3′-ethoxy-5-fluoro-2-methoxy-6-methylbiphenyl-3-yl)ethyl]-9H-purin-6-amine;N-cyclopropyl-3′-fluoro-6′-methoxy-2′-methyl-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;N-{1-[5-fluoro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-4-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-fluoro-2-methoxy-4-methyl-3-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[3-(2-aminopyrimidin-5-yl)-5-fluoro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{1-[4-Chloro-3′,5′-difluoro-6-(1H-pyrazol-4-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[5-Chloro-3-(5-chloropyridin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-Chloro-4-methyl-2-(2-morpholin-4-ylethoxy)-3-pyridin-4-ylphenyl]ethyl}-9H-purin-6-amine;N-[1-(5-Chloro-2,4-dimethyl-3-pyridin-4-ylphenyl)ethyl]-9H-purin-6-amine;N-{1-[5-Chloro-6-methyl-4′-(methylsulfonyl)-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[4-chloro-3′,5′-difluoro-6-(2-methoxypyrimidin-5-yl)biphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{5′-chloro-3″,5″-difluoro-3′-[1-(9H-purin-6-ylamino)ethyl]-1,1′:2′,1″-terphenyl-4-yl}acetamide;N-[1-(4-chloro-3′,5′-difluoro-6-pyridin-4-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;N-[1-(4-chloro-3′,5′-difluoro-6-pyrimidin-5-ylbiphenyl-2-yl)ethyl]-9H-purin-6-amine;N-{1-[4-chloro-6-(2,6-difluoropyridin-4-yl)-3′,5′-difluorobiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[5′-chloro-3″,5″-difluoro-4-(methylsulfonyl)-1,1′:2′,1″-terphenyl-3′-yl]ethyl}-9H-purin-6-amine;N-{1-[6-(2-aminopyrimidin-5-yl)-4-chloro-3′,5′-difluorobiphenyl-2-yl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-3-(2-methoxypyrimidin-5-yl)phenyl]ethyl}-9H-purin-6-amine;N-{5′-chloro-2′-methoxy-3′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-yl}acetamide;N-{1-[5-chloro-2-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl]ethyl}-9H-purin-6-amine;N-[1-(5-chloro-2-methoxy-3-pyridin-4-ylphenyl)ethyl]-9H-purin-6-amine;N-[1-(5-chloro-2-methoxy-3-pyrimidin-5-ylphenyl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-3-(2,6-difluoropyridin-4-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-4′-(methylsulfonyl)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[3-(2-aminopyrimidin-5-yl)-5-chloro-2-methoxyphenyl]ethyl}-9H-purin-6-amine;3,5′-dichloro-2′-methoxy-N-methyl-3′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;N-{1-[5-chloro-3-(2-fluoropyridin-4-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-3-(5-methoxypyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3-(6-fluoropyridin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-3-(6-methoxypyridin-3-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[3-(2-aminopyrimidin-5-yl)-5-chloro-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3′-methoxy-6-methyl-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3-(5-chloropyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-4-methyl-3-(1-methyl-1H-pyrazol-5-yl)-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3′,4′-dimethoxy-6-methyl-2-(2-morpholin-4-ylethoxy)biphenyl-3-yl]ethyl}-9H-purin-6-amine;3,3′-dichloro-N,2′-dimethyl-6′-(2-morpholin-4-ylethoxy)-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-4-carboxamide;N-{1-[5-chloro-4-methyl-3-[5-(morpholin-4-ylcarbonyl)pyridin-3-yl]-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3-(5-methoxypyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;N-(5-{3-chloro-2-methyl-6-(2-morpholin-4-ylethoxy)-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)acetamide;3′-chloro-5-fluoro-2′-methyl-6′-(2-morpholin-4-ylethoxy)-5′-[1-(9H-purin-6-ylamino)ethyl]biphenyl-3-carboxamide;N-{1-[5-chloro-3-(5-fluoro-6-methoxypyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-3-(2-methoxypyrimidin-5-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;andN-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-4-methyl-2-(2-morpholin-4-ylethoxy)phenyl]ethyl}-9H-purin-6-amine;or a pharmaceutically acceptable salt of any of the aforementioned. 20.The compound according to claim 1, which is4-chloro-3′-fluoro-3-methyl-6-[1-(9H-purin-6-ylamino)ethyl]biphenyl-2-carbonitrile,or a pharmaceutically acceptable salt thereof.
 21. A compound of claim1, selected from:N-[1-(5-chloro-2-methoxy-4-methyl-3-pyridazin-4-ylphenyl)ethyl]-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-4-methyl-3-(1,3-thiazol-4-yl)phenyl]ethyl}-9H-purin-6-amine;N-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9H-purin-6-amine;N-{1-[3-(1-acetylazetidin-3-yl)-5-chloro-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;methyl3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate;3-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N-methylazetidine-1-carboxamide;N-(1-{5-chloro-2-methoxy-4-methyl-3-[1-(methylsulfonyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-{1-[5-chloro-3-(1-isopropylazetidin-3-yl)-2-methoxy-4-methylphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-4-fluoro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-ethoxy-4-methyl-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine;N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-piperidin-4-yl-1H-pyrazol-4-yl)phenyl]ethyl}-9H-purin-6-amine;4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,1-dimethyl-1H-pyrrole-2-carboxamide;N-{1-[5-chloro-2-methoxy-4-methyl-3-(1-methylpiperidin-4-yl)phenyl]ethyl}-9H-purin-6-amine;6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridazine-4-carboxamide;5-{3-chloro-2-cyano-6-ethoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;6-chloro-3-ethoxy-2-[6-(1-hydroxyethyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;N-{1-[5-chloro-3-(5-fluoropyridin-3-yl)-2-methoxy-4-methylphenyl]propyl}-9H-purin-6-amine;N-(1-{5-chloro-2-methoxy-4-methyl-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}propyl)-9H-purin-6-amine;(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)methanol;2-(5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyridin-2-yl)propan-2-ol;N-(1-{5-chloro-2-methoxy-3-[6-(1-methoxy-1-methylethyl)pyridin-3-yl]-4-methylphenyl}ethyl)-9H-purin-6-amine;3-ethoxy-6-methyl-2-[5-(methylsulfonyl)pyridin-3-yl]-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;N-{1-[5-chloro-4-fluoro-2-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]ethyl}-9H-purin-6-aminehydrochloride;N-{1-[5-chloro-4-fluoro-2-methoxy-3-(morpholin-4-ylmethyl)phenyl]ethyl}-9H-purin-6-amine;5-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-3-isopropyl-1,3-oxazolidin-2-one;1-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-2-morpholin-4-ylethanol;6-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-4-isopropylmorpholin-3-one;4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}pyrrolidin-2-one;4-{3-chloro-6-methoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-1-methylpyrrolidin-2-one;N-{1-[4,5-dichloro-3-(1-isopropylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;N-{1-[3-(1-acetylazetidin-3-yl)-4,5-dichloro-2-methoxyphenyl]ethyl}-9H-purin-6-amine;2-(3-{2,3-dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)ethanol;N-(1-{4,5-dichloro-2-methoxy-3-[1-(tetrahydrofuran-3-yl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-(1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoro-1-methylethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-{1-[4,5-dichloro-2-methoxy-3-(1-methylazetidin-3-yl)phenyl]ethyl}-9H-purin-6-amine;N-(1-{4,5-dichloro-2-methoxy-3-[1-(2-methoxyethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-(1-{4,5-dichloro-3-[1-(cyclopropylmethyl)azetidin-3-yl]-2-methoxyphenyl}ethyl)-9H-purin-6-amine;N-(1-{4,5-dichloro-2-methoxy-3-[1-(tetrahydrofuran-3-ylmethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-(1-{4,5-dichloro-2-methoxy-3-[1-(4,4,4-trifluorobutyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-(1-{4,5-dichloro-2-methoxy-3-[1-(1,3-thiazol-4-ylmethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;N-(1-{4,5-dichloro-2-methoxy-3-[1-(3,3,3-trifluoropropyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;(3-{2,3-dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)acetonitrile;N-(1-{4,5-dichloro-2-methoxy-3-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]phenyl}ethyl)-9H-purin-6-amine;2-(3-{2,3-dichloro-6-methoxy-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidin-1-yl)propan-1-ol;N-{1-[4,5-dichloro-3-(1-cyclobutylazetidin-3-yl)-2-methoxyphenyl]ethyl}-9H-purin-6-amine;N-(1-{4,5-dichloro-3-[1-(2,2-difluoroethyl)azetidin-3-yl]-2-methoxyphenyl}ethyl)-9H-purin-6-amine;5-{3-cyano-6-ethoxy-2-fluoro-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}-N,N-dimethylpyridine-2-carboxamide;4-ethoxy-2-fluoro-3-[5-(methylsulfonyl)pyridin-3-yl]-5-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;6-chloro-3-ethoxy-2-(1-ethylazetidin-3-yl)-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;and6-chloro-3-ethoxy-2-(1-isopropylazetidin-3-yl)-4-[1-(9H-purin-6-ylamino)ethyl]benzonitrile;or a pharmaceutically acceptable salt of any of the aforementioned. 22.A composition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable carrier.
 23. A method of inhibiting anactivity of a PI3K kinase, comprising contacting the kinase with acompound of claim 1, or a pharmaceutically acceptable salt thereof. 24.A method of treating rheumatoid arthritis in a patient, comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein said treating refers to inhibiting or ameliorating.
 25. A methodof treating acute myeloblastic leukemia in a patient, comprisingadministering to said patient a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein said treating refers to inhibiting or ameliorating.
 26. A methodof treating B cell lymphoma in a patient, comprising administering tosaid patient a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof, wherein said treatingrefers to inhibiting or ameliorating.
 27. A method of treating chronicmyeloid leukemia in a patient, comprising administering to said patienta therapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, wherein said treating refersto inhibiting or ameliorating.
 28. A method of treating diffuse large Bcell lymphoma in a patient, comprising administering to said patient atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, wherein said treating refersto inhibiting or ameliorating.